How to Best Protect Patents on New Synthetic Processes and Intermediates in United States: Understanding “Material Change” exception

Here I present another Practice Pointer series, useful for Indian API manufacturers (or to that matter for any country) who are innovating and patenting new and economical processes and novel intermediates thereof and want to capitalize on US Market. The Article will discuss the infringement under the United States Process Patent Legislation and judicial decisions with particular focus on “material change” clause post which brief practice pointer would be discussed to best protect and enforce the US process patents.

What is “Material Change” exception?

§ 271(g) of the Process Patent Amendment Act (PPAA) of United States says,

“Whoever without authority imports into the United States or offers to sell, sells, or uses within the United States a product which is made by a process patented in the United States shall be liable as an infringer, if the importation, offer to sell, sale, or use of the product occurs during the term of such process patent…….

A product which is made by a patented process will, for purposes of this title, not be considered to be so made after -

(1) it is materially changed by subsequent processes; or

(2) it becomes a trivial and nonessential component of another product”.

Thus § 271(g) provides that it is an infringement of a process patent if a product made outside of United States by using the patented process is imported into United States unless the product made by the patented process is “materially changed” by subsequent processes or it becomes a trivial and nonessential component of another product.

Legislative History of the statute

Now, with respect to § 271(g), whether a change is ‘material’ is a finding of fact based upon the circumstances of the case. For example, there may be a material change to the product in a strictly chemical sense but that change may be immaterial or trivial in the overall process for producing the API product. The legislative history of this statute has provided a two-pronged test wherein:

(1) “If the only way to have arrived at “Y” (the final product) is to have used the patented process at some step, for example, producing “X” as an intermediate, Y is infringing”.

(2) “If there is more than one way to have arrived at “Y”, but the patented process is the only commercially viable way to have done so, Y is infringing”.

“If there are commercially viable non-infringing processes to have arrived at “X”, the connection between the patented process for producing the intermediate “X” and the final product “Y”, is broken, and Y would be a non-infringing product having satisfied both phases of the test.”

“The patented process may be for the process of preparing a DNA molecule comprising a specific genetic sequence…. Even if a different organism was created by this biotech procedure, if it would not have been possible or commercially viable to make the different organism and product expressed therefrom but for the patented process, the [polypeptide] product will be considered to have been made by the patented process.”

US Courts interpretation of the Statue

There are two landmark CAFC Opinions interpreting the “materially changed” defense which are important to discuss here before we present few of the practice pointers for getting the best patent protection for API processes and intermediates in US.

One of these cases is Bio-Technology General v. Genentech. Genentech Corporation obtained a US Patent claiming a plasmid coding for its hGH product. An Israeli generic manufacture Bio-Technology General (BTG) used the plasmid outside US to make the human growth hormone product, and then imported the finished product into US. BTG argued that it did not import the plasmid but a polypeptide (hGH) produced using the plasmid. Relying on the legislative history of the statute as discussed above (last para of the preceding section), the Court concluded that the plasmid was an “essential part” of the process to make the polypeptide and thus infringed patent on plasmid.

The second case is Eli Lilly v. American Cyanamid where American Cynamid made a Cephalosporin Antibiotic , Ceflacor outside of US using the patented process patended vide US 4,160,085 (‘085 Patent) for preparing an intermediate (Compound 6) used in the process of making Ceflacor. The process used to prepare the cefaclor was a nine-step process and the patented process was used in the fifth step which produced an intermediate (Compound 6). In denying Eli Lilly’s request for a preliminary injunction, the court agreed that Eli Lilly’s patented process constituted the fifth step of the process for preparing Cefaclor, but considered the Compund 6 produced in step five of the overall process was “materially changed” by the subsequent process steps. The Federal Circuit first noted that the patented process had been used outside of the US to prepare the Cefaclor. However, since there are commercially viable non-infringing processes to produce Cefaclor the patent in suit was not a “bottleneck”.The Federal Circuit then noted the differences in the Chemical structures of the two Cephem compounds, that is Compound 6 and Ceflacor. The court also pointed out the differences between the biological properties and the uses of the two compounds- the Compound 6 has no antibiotic activity and can be used as an intermediate to prepare a variety of Cephem compounds while the Cefaclor has high antibiotic activity. The Federal Circuit concluded, based on the differences between the compounds, that the cefaclor that was imported into the US was materially changed from the intermediate and thus no infringement would be found.

Practice Pointers

Below can be some of the key-take aways for the API manufactures for best protection/enforcement of the Patented process and intermediates in US:

1. Economic Advantage of the patented process over other alternatives if any:

 

Generally, the APIs can be made by more than one synthetic routes. This is an important aspect as the legislative history as well as the courts’ interpretation suggest that the alleged imported product made by using the patented process, would infringe if the patented process is the only commercially viable process to make said product. Proving the “only commercially viable process” and the economic advantage of the process over other processes would become all the more important in case the final product is a generic product as it is likely that there would be a number of synthetic routes would be available. The commercial viability and the economic significance can be proved by a number of factors, including for example, less expensive reagents, requiring less purification of the resulting crude API or using less toxic solvents, among other factors.

2. Patentability of the process and intermediate including Skillful Claim Drafting

The patentable process should at least synthesize a unique intermediate product which can be proven to be an essential component in synthesizing the final product.

The Patent has to be drafted in such a way as to give the best possible protection through the claims. For example, in Eli Lily case as discussed above, Eli Lily in its ‘085 Patent failed to show the infringement claim against American Cynamid for using an intermediate for producing Cefaclor; Eli Lily had only a “method of producing an intermediate” claim not a “method of producing a product from intermediate” claim and “an intermediate compound itself” claim. One never knows what the verdict could be had these claims been included.

The process claim(s) thus should be drafted very skillfully. The claim for a simple synthesis process can be drafted for example:

1. A process for preparation of “Y”, comprising the steps of:

a. reacting a compound of Formula __-with a compound of Formula ___ in presence of __, to give “X”, and [e.g. a process step preparing an intermediate “X” ]

b. reacting “X”, as obtained in step (a), with a compound of Formula __ in presence of __, to give “Y”. [e.g. a process step preparing a final product “Y” from “X”]

Further we can include a claim only on the intermediate compound itself. For example, simply as: A compound “X” and/or including a claim for stronger protection which can be like, “A compound “X” for use as an intermediate in preparation of “Y”. This ways, this claim will give better protection in case someone makes this intermediate by circumventing the claim 1

Conclusion

US Market has been and is one of the most sought after markets for Indian API manufactures. who have been developing novel processes/intermediates for the manufacture of important APIs and patenting in US. However only patenting is not enough, it is how well the patent is protected and enforced against the infringers to reap out the best benefits from the US market. Thus understanding of the US Process Patent Legislation and the judicial decisions on “material change” exception is essential.

About the Author:

Meenakshi Khurana, Patent Specialist at Khurana & Khurana and can be reached at: meenakshi@khuranaandkhurana.com

Practice Pointer: Form 27 Requirement in India (Statement Regarding the Working/Non-Working of Issued Patents)

It is needless to say that one core mandate of protecting one’s intellectual property is to promote the progress of science for the benefit of humankind. At the same time, it is also important to ensure that a patentee’s right of excluding others from making, selling, using, offering to sell, and importing the protected subject matter is not misused and does not lead to non-practicing or non-commercialization of the IP by anyone, which would defeat the abovementioned purpose in entirety.

One such tool for the Indian Patent Office, to prevent misuse or rather non-use of patented inventions is to seek periodic information from the patentees as to the extent of commercialization done (also interchangeably referred to as working of the invention), wherein the extent includes informing the Patent Office of the number of licenses granted (if any), revenues/sales generated from the sale/license/commercialization of the patent, parties/stakeholders involved in or responsible for actual commercialization of the patent. Working of a Patent can include but not limited to manufacturing the products in India (either by the patentee or the license) for use in India or for export, importing the patented product in India, and licensing the patent rights.

The above information is covered under Section  146(2) of the Indian Patent Act, 1970, which states that “Every patentee and every licensee (whether exclusive or otherwise) shall furnish in such manner and form and  at such intervals (not being less than six months) as may be prescribed statements as to the extent to which the patented invention has been worked on a commercial scale in India” read with rule  131(1) of the Indian Patent Act 1970 which requires that this “information should be filed every calendar year, within three months of the end of each year.” The deadline for filing this information therefore is 31’st March of each year and is applicable only to Patented inventions. The statute specifies a provision for submission of information in Form 27 regarding the details of ‘working of a patent’ granted in India, which is a statutory requirement.

The information sought by the IPO in Form 27 can be summarized as follows:

A. For not ‘working of patent’: the reasons for not working and steps being taken for ‘working of the invention’ to be provided by the patentee.

B. In case of establishing ‘working of a patent’, the following yearly information needs to be provided:

i) The quantity and value of the invention worked; which includes both local manufacturing and importation.
ii) The details to be provided if any licenses and/or sub-licenses have been granted for the products during the year.
iii) A statement as to whether the public requirements have been met partly/adequately to the fullest extent at a reasonable price.

It would be noted herein that even if the patent is commercially not worked in India, the patentee or the licensee needs to explain the reasons for not working and steps being taken for working of the invention. Such information on commercialization of patented products/method, along with other provisions such as Compulsory Licensing, at least in principle, would make the Patentee prompted to work the invention at the earliest rather than merely having a negative mindset of waiting for third parties to use/work the patented subject matter and then subsequently sue them for infringement actions and claiming their accounts of profits.

The Patent Act has also provides that if any person refuses or fails to furnish information as required under Sections 100(5) and 146, he shall be punishable with imprisonment that may extend to 6 months or fine which may go up to rupees ten lakh (one million).

Gopanjali Singh, Patent Associate, IIPRD, Gopanjali@iiprd.com

Cookie “Companies” sued by University and Exclusive Licensee thereof

Infringement suit was filed on September 7^th 2011 in Western District of Wisconsin by Brandeis University, USA (Brandeis) along with its exclusive licensee GFA brands (“Plantiffs”), against a dozen of cookie companies including Nestle USA, Inc., The Pillsbury Company, LLC, Keebler Co., Famous Amos Chocolate Chip Cookie Company, LLC, East Side Ovens, Inc., Murray Biscuit Co. LLC, Voortman Cookies Ltd., Bremner Food Group, Inc., Wessanen U.S.A., Inc., Cookie Specialties, Inc., Topco Associates LLC (collectively “Defendants”) for illegally using a formula that manipulates the balance between good cholesterol and bad cholesterol, providing “significant health improvements”.

US patent 5,843,497 issued on December 1998 (Patent ‘497) and its family patent US patent 6, 630,192 issued on October 2003 (Patent ‘192) assigned to Brandeis University discloses method of “Increasing the HDL Level in the HDL/LDL Ratio in Human Serum by Balancing Saturated and Polyunsaturated Dietary Fatty Acids”. Brandeis granted a worldwide, sole and exclusive license of ‘497 and ‘192 patents, with the right to sublicense to GFA Brands. This license grants GFA Brands the right to sue for infringement of the ‘497 and ‘192 patents.

The claimed inventions in the ‘497 and ‘192 patents are directed to fats and fat blends that decrease low-density lipoprotein cholesterol (LDL) and increase high-density lipoprotein cholesterol (HDL) in the human serum. This adjustment/balance of the LDL/HDL ratio according to the claimed inventions results in significant health benefits.

Claim(s) Proposed to be Infringed by Companies:

Cookie companies mentioned above are said to have found to be infringing one or more claims of either ‘497 or ‘192 patent or both, by manufacturing, using and marketing the products in US claimed in the patented invention. Typically, independent claim 7 of ‘497 patent and claim 1 of ‘192 patent are found to be infringed by cookie manufacturers.

Claim 7 of ‘497 patent recites:

“7. A prepared food product, comprising a cholesterol-free fat composition suitable for human or animal ingestion for increasing the HDL concentration and the HDL/LDL concentration ratio in the blood serum, comprising one part by weight polyunsaturated fat and at least one part by weight cholesterol-free saturated fat, where said fat composition comprises linoleic acid and at least one saturated fatty acid selected from the group including lauric acid, myristic acid, and palmitic acid, said linoleic acid constituting between 15% by weight and 40% by weight of the fat in said fat composition and said saturated fatty acid constituting between 20% and 40% by weight of the fat in said fat composition.”

Claim 1 of ‘192 patent recites:

“1. A cholesterol-free margarine, comprising a blend of at least one polyunsaturated fat and at least one saturated fat, forming a cholesterol-free blended fat composition, wherein said blended fat composition comprises between 15% by weight and 40% by weight linoleic acid, between 20% and 40% by weight saturated fatty acids, wherein said saturated fatty acids comprise at least one saturated fatty acid selected from the group consisting of lauric acid and palmitic acid, and no more than 1% elaidic acid or other unnatural trans fatty acids by weight; wherein the ratio of polyunsaturated fatty acids to saturated fatty acids is from 0.5:1 to 2:1, and wherein said cholesterol-free margarine is suitable for ingestion by a human as a food product and for increasing the HDL concentration and the HDL/LDL concentration ratio in the blood serum following ingestion by a human.”

Cookies, cookie doughs and products used in making/producing such cookies and selling under company’s respective brand names include for example:

-          Nestle’s: Tollhouse Chocolate Chip Cookie Dough;

-          Pillsbury’s: Grands Flaky Layers Reduced Fat Biscuits and Reduced Fat Crescent Rolls; Topco’s: ShurFine® Vanilla Wafers and ShurFine® Animal Crackers;

-          East Side Ovens’s: Cranberry Orange Cookies;

-          Keebler’s: Chips Deluxe Chocolate Lovers Cookies, Chips Deluxe Oatmeal Chocolate Chip Cookies, and Chips Deluxe Rainbow Cookies;

-          Famous Amos’s: Bite Size Chocolate Chip & Pecans Cookies and Chocolate Chip Cookies; Murray’s: Murray Sugar Free Chocolate Chip Cookies;

-          Voortman’s: Fudge Striped Oatmeal Cookies;

-           Bremner’s: Rippin’ Good® Vanilla Wafers and Rippin’ Good® Animal Cookies

-          Wessanen’s: Baker’s Row Mini Oyster Crackers;

-          Cookie Specialties’: Matt’s® Oatmeal Raisin Cookies

which have been claimed to be infringing at least Claim 7 of the ‘497 patent either directly or indirectly under the doctrine of equivalents.

Similarly, it has also been mentioned that cookies and/or products for making the same by companies like Unilever, Keebler and Bremner, constitute to wilful infringement of at least Claim 1 of the ‘192 patent either directly or indirectly under the doctrine of equivalents. Some of the products of the specified companies include but for example:

-          Unilever’s: Promise Buttery Spread;

-          Keebler’s: Vanilla Wafers and Mini Vanilla Wafers;

-          Bremner’s: Rippin’ Good® Vanilla Wafers

Plaintiffs seek relief from the court about its judgement and respective award of damages from the cookie companies for wilful infringement of their patents. We look forward to the analyze the final outcome on infringement but believe that this trend of university’s exclusive licensee suing potential infringers would grow on a larger scale going forward, with more technology transfer offices looking forward to grant exclusive licenses or sell the IP rights in totality.

Minusmita Ray, Patent Associate, IIPRD, Minusmita@iiprd.com

Technology Transfer/Licensing Opportunity of Crop/Agri Technologies with Syngenta

IIPRD is among the leading Indian IP Consulting Firms focusing on Technology Transfer and Licensing for numerous Indian and Global Corporates and Research Institutes. IIPRD is highly active in the Technology Transfer and Licensing of Patent Backed Technologies/IP’s in the domains of Pharmaceutical, Life Sciences, Diagnostics, Biotechnology, Telecommunications, Software and Medical Devices among others.

Syngenta is one of the world’s leading companies with more than 26,000 employees in over 90 countries and has a core focus on agri-business committed to sustainable agriculture through innovative research and technology.

Syngenta is looking for innovative technologies in specific grower solutions domain and is interested in partnership as well as in-licensing/buying technologies. It is an excellent opportunity for the Indian/ Foreign companies, Universities and Institutes for technology transfer/out-licensing/commercialization of their technologies in the following technology areas.

Types of opportunities that are of interest to Syngenta:

• Access to technology (e.g. purchase or license)
• Collaborative proposals
• New products or concepts for agriculture or lawn and garden

Syngenta is primarily looking for grower solutions comprising genetics, chemistry and/or adjacent technologies for core crops in the areas of:

• Weed control
• Disease control
• Insect control
• Nematode control
• Abiotic stress tolerance (e.g. drought, heat, nitrogen)
• Breakthrough yield
• Output quality (e.g. shelf life, taste, etc.)

In order to achieve this, Syngenta is also interested in enabling technologies supporting:

• Formulation technologies
• Application technology
• Precision agriculture
• Seed technologies (seed coating, seed priming, etc)
• Breeding technologies (double haploids, hybridization systems, quantitative genetics, etc.)
• Phenotyping technologies for field, greenhouse and lab
• Bioinformatics
• Omics (genomics, proteomics, metabolomics, epigenetics, etc.)
• Genome engineering (plant transformation, recombination, trait stacking, RNAi, etc.)
• Expression technologies
• Analytical techniques (small molecule, protein, polymer)
• Logistics (seed sowing, liquid handling, sample handling, data capture)
• Modeling (chemical design, environmental studies, field resistance)
• Chemical process technology.

IIPRD requests all the interested companies/institutes/individuals having the above mentioned technologies to write us at commercialization@iiprd.com or Dayanand@iiprd.com and share the non-confidential data of the same with so that we can, if desired, take forward the discussion with Syngenta for a potential licensing opportunity.

Gevo – Butamax back and forth Ongoing Infringment Lawsuits

It looks like a never ending infringement lawsuits between Gevo Inc. and Butamax Advanced Biofuels LLC on IP rights of bio-isobutanol, a well known biofuel.

On September 13, 2011, Gevo Inc. was granted two patents by USPTO that involved technologies enabling low-cost, high-yield production of bio-based isobutanol. Gevo’s patent 8,017,375 (‘375), “Yeast Organism Producing Isobutanol at a High Yield” focuses on the modification of yeast to produce isobutanol instead of ethanol. Patent 8,017,376 (‘376), “Methods of Increasing Dihydroxy Acid Dehydratase Activity to Improve Production of Fuels, Chemicals, and Amino Acids” covers enzymatic steps on isobutanol production from yeast.

Office action response of Gevo’s 375 patent

The Examiner had rejected claims 131-149 of Gevo’s application over US 7,851,188 (of Donaldson/Butamax) citing that it disclosed the genes encoding the enzymes for isobutanol synthesis. On 28 April 2011, Gevo made a response to the rejection by the Examiner stating Butamax had NOT disclosed pdc disruption. Further for pdc disruption, the Examiner cited van Maris (2004), and thus gave a 103 rejection. Gevo overcame this by adding the requirement: an .alpha.-ketoisovalerate decarboxylase from Lactococcus lactis to catalyze the conversion of .alpha.-ketoisovalerate to isobutyraldehyde.

Claim 1 of issued US 8,017,375 states:

A recombinant yeast microorganism for producing isobutanol, the recombinant yeast microorganism comprising an isobutanol producing metabolic pathway, wherein said isobutanol producing metabolic pathway comprises the following substrate to product conversions: (i) pyruvate to acetolactate; (ii) acetolactate to 2,3-dihydroxyisovalerate; (iii) 2,3-dihydroxyisovalerate to .alpha.-ketoisovalerate; (iv) .alpha.-ketoisovalerate to isobutyraldehyde; and (v) isobutyraldehyde to isobutanol; wherein said recombinant yeast microorganism expresses: (a) an acetolactate synthase to catalyze the conversion of pyruvate to acetolactate; (b) a ketol-acid reductoisomerase to catalyze the conversion of acetolactate to 2,3-dihydroxyisovalerate; (c) a dihydroxy acid dehydratase to catalyze the conversion of 2,3-dihydroxyisovalerate to .alpha.-ketoisovalerate; (d) an .alpha.-ketoisovalerate decarboxylase from Lactococcus lactis to catalyze the conversion of .alpha.-ketoisovalerate to isobutyraldehyde; and (e) an alcohol dehydrogenase to catalyze the conversion of isobutyraldehyde to isobutanol; wherein the recombinant yeast microorganism has been engineered to disrupt, mutate, or delete one or more endogenous pyruvate decarboxylase (PDC) genes, wherein said recombinant yeast microorganism has reduced endogenous PDC activity as compared to the corresponding yeast microorganism that has not been engineered to have reduce endogenous PDC activity, and wherein said recombinant yeast microorganism produces: (A) isobutanol at a yield which is at least 10% of the theoretical yield of isobutanol from glucose; and/or (B) ethanol at a yield which is 1.8% or less of the theoretical yield of ethanol from glucose.

The first claim of the Butamax ’188 patent states:

A recombinant microbial host cell comprising heterologous DNA molecules encoding polypeptides that catalyze substrate to product conversions for each step below: i) pyruvate to acetolactate; ii) acetolactate to 2,3-dihydroxyisovalerate; iii) 2,3-dihydroxyisovalerate to .alpha.-ketoisovalerate; and iv) .alpha.-ketoisovalerate to isobutyraldehyde; wherein said microbial host cell produces isobutanol; and wherein a) the polypeptide that catalyzes a substrate to product conversion of pyruvate to acetolactate is acetolactate synthase having the EC number 2.2.1.6; b) the polypeptide that catalyzes a substrate to product conversion of acetolactate to 2,3-dihydroxyisovalerate is acetohydroxy acid isomeroreductase having the EC number 1.1.1.86; c) the polypeptide that catalyzes a substrate to product conversion of 2,3-dihydroxyisovalerate to .alpha.-ketoisovalerate is acetohydroxy acid dehydratase having the EC number 4.2.1.9; d) the polypeptide that catalyzes a substrate to product conversion of .alpha.-ketoisovalerate to isobutyraldehyde is branched-chain .alpha.-keto acid decarboxylase having the EC number 4.1.1.72.

Prior to this case, Butamax on January this year, filed two infringement lawsuits against Gevo, alleging Gevo unlawfully used Butamax technology regarding the 7,851,188 (‘188) patent issued on December 2010 and its related patent related 7,993,889 (‘889) granted on Auhust 9, 2011. The patent ‘188 covers biocatalysts that Butamax developed to produce isobutanol. Second patent ‘889 covers methods for low-cost production of biobutanol.

Butamax stated that “Butamax and its owners were the first to develop this technology and it is our belief that the protection of intellectual property serves the best interest of the biofuels industry, our customers and the U.S. energy policy.”

However, Gevo highlighted that it did not use the technology claimed in Butamax’s patents, but employed its own distinct technology, GIFT® (Gevo Integrated Fermentation Technology®), which is covered by more than 150 patent applications that enables the efficient production of isobutanol.

Later Gevo filed a lawsuit against Butamax and its parent company DuPont in charge of infringing Gevo’s two newly-issued patents (‘375 and ‘376). The invention described in the two patents involves Gevo’s unique technology to produce isobutanol. Hence the lawsuit is based on Butamax’s own publications describing their use of the technology that Gevo invented first and for which they have received patents.

In regards to this infringement suit, Paul Beckwith, CEO of Butamax stated:

“When Butamax makes isobutanol, we do not use the technology claimed in the Gevo patents. We are so confident about this, that we offered Gevo an opportunity to independently verify that Butamax does not infringe either of these patents. Ignoring both our offer to verify and the facts, Gevo instead filed its lawsuit.”

Butamax further added that it plans to seek legal relief from this frivolous suit and was confident in the eventual result from the court.

The Gevo patents are for a limited technology, which when applied for isobutanol production, are dominated by Butamax’s intellectual property and are invalid, as claimed by company officials.

Moreover Gevo’s patents are based on Butamax’s technology and cannot be practiced to make isobutanol without infringing Butamax’s rights. Indeed, Gevo’s patents include clear evidence of Gevo’s use of Butamax’s technology and infringement.

Continuing the chain of law suits Gevo further filed two petitions in USPTO to re-examine Butamax’s both patents ‘188 and ‘889 stating that the two patents were already known in the scientific community and were already been invented by others before Butamax applied for the patents.

For patent ‘188 of Butamax, Gevo cited references under light of obviousness under 35 USC 103 of the ‘188 patent. The references include US 2004/0146996 published by Yocum, a Ph.D. thesis “Formation of Amino Acid Derived Cheese Flavour Compounds”, 2004,  by Smit, Nakamura’s US 6,013,494 on producing 1,3 propanediol by recombinant microorganisms, a screen capture from the ExPASy Proteomics Server and also a citation from 3rd edition of Lehninger Principles of Biochemistry. None of these were cited the prosecution history of patent ‘188.

Secondly, for patent ‘889, Gevo identified references anticipating claims 1, 3, 11 and 16-19 based on Larroy, Chemico-Biological Interactions (2003), which discloses the pathway from pyruvate to isobutanol. Apart from these, other references include Yocum’s US 20040146996 and Bekkaoui, Current Genetics (1993).

Key take aways:

It is pretty strange for small companies to go against chemical giants like Dupont or its subsidiary companies like Butamax. However, this patent fight seems to signal the growing potential importance of bio-butanol for the biofuel and chemical industries worldwide. In addition, it also gives us a view that if patents are quite strong in their claims and use novel technologies, then any company unlawfully adapting the same technology will be infringing the invention, no matter how big it is.

Minusmita Ray, Patent Associate, IIPRD, Minusmita@iiprd.com

Practice Pointer Series: Brief on Patenting Diagnostic Methods in India

Patenting of medical methods is prohibited in India according to Section 3 (i) of the Indian Patent Act, which states that “any process for the medicinal, surgical, curative, prophylactic [diagnostic therapeutic] or other treatment of human beings or any process for a similar treatment of animals to render them free of disease or to increase their economic value or that of their products.” This flexibility has been conferred by TRIPS in its Article 27(3) which states that “members may also exclude from patentability diagnostic, therapeutic and surgical methods for the treatment of humans or animals”.

Among various medical methods as described in Section 3 (i), such as surgical and therapeutic methods, patentability of diagnostic methods in particular has been questionable and is not objectively interpreted.

This article tries to focus on understanding the Indian patent scenario with respect to patenting of diagnostic methods and providing some key points for more efficient protection of the same.

The Indian “Manual of Patent Office Practice and Procedure” describes that Diagnosis is the identification of the nature of a medical illness, usually by investigating its history and symptoms and by applying tests. Further the Manual explains that determination of general physical state of an individual (for example a fitness test) is not considered to be diagnostic if it is not intended to identify or uncover pathology. Thus, the diagnostic methods excluded from Patentability include methods which determine or identify existence of a disease or disorder. However, if a method does not include the identification of a disease or disorder, then the method would be patentable. Had this been the case, the scope of diagnostic methods excluded from patentability would have been construed very narrowly. However the Indian Patent Act provides a flexibility in a form such that only diagnostic methods practiced on the living body are not patentable and the diagnostic methods performed on tissues or fluids which have been permanently removed from the body are not be excluded, that is the in-vitro methods are patentable.

Thus, the Patent Scenario in Indian is similar to European Patent Law where according to Article 52(4) of the EPC, in-vitro diagnostic methods are found to be patentable. However the exact scope of such exclusion is not clearly defined at the moment due to the lack of the interpretation of the Courts unlike in Europe where the extent of the auspices of patentable subject matter is litigated a large number of times in Courts. Under US Patent Law, all medical methods including Diagnostic Methods are patentable.

Additionally, under the Indian Patent Law, there have been instances when the examiners have rejected the in-vitro diagnostic methods too under the pretext of Section 3 (d) of the Act citing lack of inventive step involving “mere use of a known process”.

For example, if the detection method  per se as well as the biomarker in the sample are already known and the proposed invention only identifies use of the marker in the detection of a disease, there are high chances that the method would not be patentable. Thus, where the method involves a novel biomarker or one or more novel detection method steps, the chances of patentability become high. Indian Granted Patent IN 228031, for example, claims a rapid method for heat mediated ELISA characterized in using an activated solid support for detection of minute quantities of biomolecules such as antigen, antibody etc. The method has a profound technical advancement of reduction in the total time required for ELISA to around 3 h. Another Indian granted Patent IN 223553 claims an in vitro method of determining an expression level of a plurality of genes in the sample consisting of gene No. 1 to 562 in predicting the prognosis of a biological condition in animal tissue. The Indian Patent IN 220274 claims a method for detecting a risk of gastro esophageal reflux disease on assaying the analytes pepsinogen I, fasting gastrin-I7 and a marker for Helicobacter pylori infection. Another Indian Patent claims a method of for detecting antibodies to INGAP 104-118 peptide contacting test sample with the peptide bound to solid support. The Indian Patent IN 233723 claims a new Scintillation Proximity Assay for the detection of peptidoglycan synthesis. Thus we have seen that all these granted patents describe one or more novel procedural steps in the diagnostic methods described therein. However, subject to the lack of the exact scope, the patenting of diagnostic methods in India is still decided more often on a case-by-case basis.

 

Conclusion

The diagnostic methods are patentable in Indian provided they are not practiced on living body and are performed on tissues or fluids which have been permanently removed from the body. Further, for the best protection, either the biomarker or any of the steps involved in the method should be novel, involving “inventive step” and deviating away from the “mere use of the known process” rejection. The scope of the Patentability of Diagnostic methods in India is still not clearly defined due to the lack of the interpretation of the Courts unlike in Europe where the extent of the auspices of patentable subject matter is litigated a large number of times in Courts.

About the Author:  Meenakshi Khurana, Patent Specialist, IIPRD and reachable at Meenakshi@iiprd.com or Meenakshi@khuranaandkhurana.com

Adams Respiratory Therapeutics, Inc. Vs. Perrigo Co.- Dispute Related to Pharmacokinetic Claim Terms

Adams Respiratory Therapeutics, Inc. Vs. Perrigo Co.- Dispute Related to Pharmacokinetic Claim Terms

Adams Respiratory Therapeutics, Inc. (Adams)-“Plaintiff” holds patent 5,372,252 (‘252 patent), which covers an extended release formulation containing guaifenesin (an expectorant used to thin, loosen, and helps expel mucus that causes congestion). Adams markets Mucinex® which is the preferred embodiment of the ’252 patent. Perrigo Co. (Perrigo)-“Defendant” sought FDA approval for a generic version of Adams’ product, Mucinex® to market 600 mg guaifenesin extended release tables, with a paragraph IV certification to the ‘252 patent. Adams sued Perrigo for infringement of claims 26, 33, 34, and 39 of the ’252 patent. After construing the claims, the District Court granted Perrigo summary judgement of non-infringement.  But later on appeal by Adams, the Federal Circuit panel reversed the grant of summary judgement and remanded because the court based its judgment of noninfringement on an erroneous claim construction.

The claim terms in this dispute related to pharmacokinetic parameters.  Such parameters are used to characterize the rate and extent of absorption of the active pharmaceutical ingredient (API).  The primary term at issue was Cmax which indicates the maximum concentration of the API following dosing.

Basically, the dispute was over the meaning of the term “equivalent” in independent claim 24, and claims 26, 33, 34, and 39 depend on claim 24. Claim 24 recites:

“24.  A modified release product having two portions, wherein a first portion comprises a first quantity of guaifenesin in an immediate release form which becomes fully bioavailable in the subject’s stomach and a second portion comprises a second quantity of guaifenesin in a sustained release form wherein the ratio of said first quantity to said second quantity provides a Cmax in a human subject equivalent to the Cmax obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period and wherein said product also provides therapeutically effective bioavailability for at least twelve hours after a single dose in a human subject according to serum analysis.”

 

“Equivalent Cmax”

The District Court construed “equivalent” as “within 80% to 125% of the value with which it is being compared, at a 90% confidence interval,” basing its construction on Adams’ statements during reexamination that ‘equivalent’ meant ‘the FDA bioequivalence guidelines’[i.e., the FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations," which reflect both an 80 to 125% range and a 90% confidence interval]. But Adams argued that ‘equivalent’ meant within the 80 to 125% range, and not 90% confidence interval. Adams further stated that % confidence interval, makes sense when seeking FDA approval, but not when proving infringement.

In response to Adams statement, Perrigo argued that 80 to 125% range “means absolutely nothing in terms of establishing bioequivalence under FDA’s guidelines without the 90% confidence interval, as, among other things, it is the confidence interval itself that must fall within the 80-125% range.”

The court agreed with Adams and construed “equivalent” to require a Cmax that is 80% to 125% of the value to which it is being compared and not meant (“equivalent”), meeting all of the requirements of the FDA’s bioequivalence guidelines.

Adams compared the accused product of Perrigo to Mucinex by citing the concept of A=B=C, therefore, A=C. Adams’ argued that the accused product was bioequivalent to Mucinex, and Mucinex was bioequivalent to a standard immediate release (“IR”) product, then the accused product had a Cmax equivalent to the IR product.

Adams also presented PK and Cmax data, which made it more evident that Perrigo’s product was equivalent to Adam’s product. In this way, summary judgement for Perrigo was therefore reversed on this ground.

 

Construction of “Bioavailable”

Next, Perrigo highlighted that the claim term “Bioavailable” of the ‘252 patent is ambiguous in its meaning. Perrigo’s alternative way to seek summary judgement of noninfringement by Distirct court was also rejected by Federal circuit. The dispute revolved over the fact on whether the phrase “fully bioavailable in the subject’s stomach” meant “both release and availability in the stomach for absorption, wherever that absorption might occur.”

Perrigo did not agree on the point of infringement, that the ANDA product with IR portion of guaifenesin would become “fully bioavailable in the subject’s stomach” as claimed in claim 24 of Adams patent. Perrigo further argued stating “bioavailable” is commonly understood to mean absorption, thus requiring the guaifenesin to be absorbed in the stomach.  But as guaifenesin is primarily absorbed in the small intestine, this construction of “Bioavailable” would not suffice a finding of infringement.

In response to this, Adams pointed to the specification, which repeatedly states that the IR portion of guaifenesin is released in the stomach, but never states that it is absorbed in the stomach. The Federal circuit agreed to Adams’ consistency in using/construction of this term in the specification and denied Perrigo’s approach. The panel highlights that although the specification never expressly defines bioavailable, it uses the term when describing the availability of the drug for absorption, not the actual absorption.

 

Doctrine of Equivalents

Finally, Adams argued that Perrigo’s ANDA product would infringe the dependent claim 34 under the “doctrine of equivalents”.

Claim 34 recited:

“34.  The modified release product of claim 26 [which claims the modified release product of claim 24 wherein the total quantity of guaifenesin is 600 mg] wherein the Cmax of said product is at least 1000 ng/mL and said product has an AUCinf of at least 3500 hr*ng/mL.”

This appeal of Adams to show infringement under the doctrines of equivalent was agreed by the Federal Circuit panel that an amount of 3494.38 hr*ng/mL was equivalent to 3500 hr*ng/mL.

 

Conclusion:

We all know that a particular patented drug for commercialization/marketing finally needs a FDA approval to enter the medical market. Hence, according to me it is practically meaningless to specify a numerical range without a confidence interval and not importing/considering the FDA values and guidelines into the claim construction. However, I would appreciate Adams’ explanation over the numerical values of doctrines of equivalent because biologically speaking, such minor variations in pharmacokinetic parameters are practically acceptable in humans and animals.

Minusmita Ray, Patent Associate, IIPRD. Minusmita@iiprd.com

Form 3 – Some Reflections

Lately, we have been receiving a number of queries from our International clients related to the submission of Form 3 at the Indian Patent Office. The queries range from timing, frequency, content and information included in the Form 3. The aim of this article is to quickly put forth salient features of the Section 8, bring some light on the procedure and formulate some general guidelines which should be adhered to.

Form 3 is a Statement and Undertaking regarding Foreign Applications which is required to be submitted to the Indian Patent Office under Section 8. Section 8 is defined as:

8 (1) Where an applicant for a patent under this Act is prosecuting either alone or jointly with any other person an application for a patent in any country outside India in respect of the same or substantially the same invention, or where to his knowledge such an application is being prosecuted by some person through whom he claims or by some person deriving title from him, he shall file along with his application-

(a) a statement setting out the name of the country where the application is being prosecuted, the serial number and date of filing of the application and such other particulars as may be prescribed; and

(b) an undertaking that, up to the date of the acceptance of his complete specification filed in India, he would keep the Controller informed in writing, from time to time, of details of the nature referred to in clause (a) in respect of every other application relating to the same or substantially the same invention, if any, filed in any country outside India subsequently to the filing of the statement referred to in the aforesaid clause, within the prescribed time.

8 (2) The Controller may also require the applicant to furnish, as far as may be available to the applicant, details relating to the objections, if any, taken to any such application as is referred to in sub-section (1) on the ground that the invention is lacking in novelty or patentability, the amendments effected in the specifications, the claims allowed in respect thereof and such other particulars as he may require.

In simple words Form 3 is submitted to furnish information/actions/status relating to the patent applications filed in other countries for a particular Indian Patent Application. Further, Section 8 requires that the Applicant will keep the patent office informed (in Form 3) up to the date of grant of patent in India in writing the details regarding corresponding applications for patents filed outside India from time to time.

The Proper and timely submission of the Form 3 has gained all the more importance following a famous Chemtura Case when interim injunction was revoked against Chemtura Corporation by a Division Bench of Delhi High Court in a patent infringement suit involving one reason as the Non–compliance with Section 8(1) and 8 (2). In brief, Chemtura Corporation filed first Form 3 while filing Indian National Phase Application on 21^st June 2001. After that, in spite of the changes in the status of the Applications in other countries particularly in US and Europe where Rejection Letters were issued and claims were narrowed down, no further Form 3 updating the status was submitted in accordance with Section 8(1). Further in accordance with Section 8(2), the Controller asked to furnish the details of the Examination Reports of countries like US, EP and JP, which Chemtura failed to comply with.

Though Indian Patent Act has defined the Section 8 mentioning the details regarding the submission of Form, the utmost clarity on the frequency, timing and the content/information relating to the subsequent Form 3 is required. We, at our Firm Khurana & Khurana, typically follow the general guidelines to adhere to the requirements of Section 8(1) and 8(2) as follows:

Timing, Frequency and Content of Form 3

• First Form 3 is filed along with Filing the Application in India mentioning the countries, Application Nos., Publication nos. (if applicable) and the current status of the Application in respective countries.
• Next within six months of filing the Application, the second and updated Form 3 mentioning the changes in the status if any is filed.  The status can be “Published”, “Awaiting Publication”, “Undergoing Examination”, “First Examination Report Received”, “Withdrawal of Application”, “Granted” etc and the same is updated from time to time up to the date of grant. Writing “Pending” as the Status of an application should be avoided as the decision of the Chemtura Case holds that “status” does not mean “pending” or “dismissed”. “
• Then, we advise our clients to inform us the updated status of the Application in any country within six months of that status change. If desired, we also follow up with clients six months after their previous Form 3 submission date.
• We also strongly advise our clients to submit the copies of the Examination Reports, Responses to the Objections, Amendments etc.

Information of which Countries

• We submit information of all Foreign Applications whether they are PCT National Phase Applications or the Convention Applications based on Paris Convention taking priority within 12 months.

In conclusion, submission of Form 3 should not be held lightly as little delay or any missing status can cost the patent rights in India, as one of the grounds of the Revocation, Pre- & Post- Opposition of the Patent/Patent Application is non-compliance with the Section 8 of the Indian Patent Act.

About the Author: Ms. Gopanjali Singh, Patent Associate at Khurana & Khurana and can be reached at: Gopanjali@khuranaandkhurana.com

E-Filing of Trade Mark Application and Related Documents with Indian Trade Marks Registry to be made mandatory

Indian Trade Marks Registry has on 03^rd November 2011, published on their website Gazette Notification dated October 13,2011 which states that after expiry of forty five days from the date (which falls on 18 Dec 2011) on which this notification is published, the e-filing of trade marks applications and related documents will be made mandatory after considerations of objections and suggestions received from public in this regard. As an impact of this, if one files a Trade Mark application online, he/she will:

• Receive a trade mark application number immediately

• Receive an On-line verification to assure error-free filing and obtain the filing date

• Speed up the registration process

• Print the completed application data and receive fee acknowledgement

• Save the data locally onto the PC

• Be able to recall the contact details for subsequent applications

 

About the Author: Mr. Sagar Gupta, a Trade Mark Associate at Khurana & Khurana, IP Attorneys and can be reached: Sagar@khuranaandkhurana.com.

Technology Transfer Opportunities for Pharma/Biotech/Diagnostic Companies in the SME Sector

IIPRD (IIPRD) is among the leading Indian IP Consulting Firms focusing on Technology Transfer and Licensing for numerous Indian and Global Corporates and Research Institutes. IIPRD is highly active in the Technology Transfer and Licensing of Patent Backed Technologies/IP’s in the domains of Pharmaceutical, Life Sciences, Diagnostics, Telecommunications, Software and Medical Devices among others.

IKP Knowledge Park: IKP Knowledge Park (formerly known as ICICI Knowledge Park) is a non-profit Science and Technology Park based in Hyderabad, and is recognized as the premier biotech park in India. It is playing an active role in developing the biotechnology and pharmaceutical industries.

Foundation for MSME Clusters: Also known as FMC, the body is a non-profit registered Trust conceived by the Entrepreneurship Development Institute of India (EDII), Ahmedabad, India with technical support from the United Nations Industrial Development Organization’s Cluster Development Program in India. FMC strives towards making cluster initiatives inclusive with the help of a pool of distinguished national and International experts.

IIPRD is happy to announce its association with IKP Knowledge Park and The Foundation of MSME Clusters for being its Official Partner for scouting for new and innovative technologies (preferably backed by a strong Patent Portfolio) Technology Transfer opportunities for Small-Medium Size Pharmaceutical Companies. The ultimate aim is to accelerate the development of innovative companies in biotech, pharma, diagnostics and medical device areas through cluster development, technology acquisition and innovation fostering.

It is an excellent opportunity for the Indian/ Foreign companies, universities and Institutes for technology transfer/out-licensing/commercialization of their technologies in the following technology areas.

Technology Areas:

1.  Therapeutics & vaccines in phase 1 clinical trials (infectious diseases, cancer)
2. Biosimilars with significant data for regulatory approval (MAbs, therapeutic proteins)
3. Point of care diagnostics that can be low priced
4. Molecular PCR diagnostics – infectious diseases, genetic diseases
5. ELISA based diagnostics – infectious diseases, genetic diseases
6. Rapid diagnostics (paper strip tests)
7. Enzymes for diagnostics biochemical tests (GOD, POD, etc)
8. Enzymes with industrial applications
9. Economic and green production of pharmaceutical intermediates and API’s
10. Cardiac stents improvements, designs
11. Inexpensive medical devices

In brief, the mandate of the exercise is to identify technologies in one or more of the above highlighted technology verticals and present them to established and interested group of In-Licensees/Buyers of the technologies. Product or process Technologies of potential out-licensees/sellers, which are either Corporates or Individuals, having adequately supporting clinical data or commercial use data relating to the respective technology, are welcome to send their technologies to us for brief evaluation post which we would be sharing these technologies with potential in-licensees/buyers in India.

The potential technologies would be showcased in January 2012 in Hyderabad and Ahmedabad, India and we therefore request all interested companies having technologies in the above mentioned categories to write to us at Dayanand@iiprd.com or iiprd@iiprd.com or contact Dayanand Reddy at 0120-2342010.

Mr. Dayanand Reddy

IIPRD

IFAIA Centre, S/20-22,
Greater Noida Shopping Plaza
UPSIDC Site – IV,
Plot No. S-7/2, Kasna Road
Greater Noida – 201 308, UP,
National Capital Region, India.

Specific Requirements:

API and intermediate production:

1. Few intermediates which are imported from China. Indian companies are interested in cost-effective methods of manufacture that can be in-licensed. Examples: 2,4-Dichloroflurobenzene (Intermediate for Ciprofloxacin), 6 – AminoPenicilic Acid (6-APA; intermediate for Peninicillin),  Erythromycin (fermentation intermediate)Vitamin C, Difluorobenzene(Intermediate for Flucanazole).
2. Biocatalysis for stereoselective reduction.
3. Chiral synthesis, enzymatic stereoreduction, Novel catalysts to make process more efficient, Stoichiometric yield improvement (theoretic/atom yields).
4. Cheaper process, green processes, more efficiency. Raw materials. Want to enter new markets-open to new APIs.
5. Custom synthesis of Impurity/metabolite: Cost effective synthesis, novel methods of synthesis.
6. Process improvements, Intermediate manufacture.
7. Open to considering new synthesis pathways. Open to making new analogs of APIs.
8. Open to new processes that are more economical. Reduction, chloromethylation and bromination green technologies, Methylation of phenols, Water based methylation using methanol and phase transfer catalysts.
9. Ketone and amine technology for statins.

Formulations and drug delivery:

1. NDDS, Novel formulations, production technologies (Directly Compressable Granulation technology; Dissolution Technology (key requirement))
2. Gastric retentive technology (GRT). Transdermal patches-HRTs, hypertension. Liquid orals technologies. Solid oral- controlled release, Intra rumenal capsules. Dry powder inhalation products
3. NDDS for asthma drugs, for respiratory delivery
4. Mouth dissolving tablets

Biotechnology:

1. High value, low volume.  Energy, probiotics, waste water treatment etc.
2. Childhood vaccines/ candidates, adult vaccines, novel vaccines, novel fermentation technology, adjuvants, vaccine delivery, cold chain breaking technologies..novel formulations
3. Want microbial identification techniques
4. High yield vectors to produce monoclonal antibodies, better production techniques. Similar techs for biosims
5. Most robust technological systems for manufacturing, processing and analytical advantages(HPLC, PCR, etc-fewer steps). Methods for increasing yields, or reducing down-stream processing costs. Antibodies for purification: product specific. Raw materials too high-disposable bioreactors, plastics, pipettes, etc.New vaccine candidates, novel adjuvants, novel expression systems, Bacterial or yeast expression systems for influenza antigens, HPV antigens, MAbs, etc
6. Monoclonal antibodies-biosimiliar. Open to acquiring new area (oncology focus, TuMabs). Surface resonance frequence meters for testing Mabs.
7. Genetically modified organism for yielding DHA, less expensive raw materials
8. Effluent treatment.
9. Fermentation based technologies, technologies that can improve conjugation of vaccines, anything that can increase yields, etc.better vaccines that. Better adjuvants, better stability appearance, etc
10. Fermentation based technology for pharma – Immuno-surpressions. Seretiopeptidase, Nattokinase, Fungal-destase, acitic protease, Lectase (enzymes), Improved versions. They have 40,000 litre fermentation capacity, which is ready, which they want to use. Sub-merge biotechnology. Good vaccine technology, like polyvalent, penta-valent. They don’t want to be disease specific. Open for multiple disease areas
11. Vertical integration. Biofuels: Jatropha seed to oil. Value added technologies. (for e.g. decrease toxicity in seed cake). Anything that adds value to any step in the biodiesel production. Any clean energy technology- algae, etc. Resin column technologies, hydrodynamic conversion, catalytic depolymerization. Nutraceuticals:  innovative herbal extraction, low- value, high value plant based products.

Diagnostics:

1. Access to good quality MAbs. Immunoturbidometry techniques.Open to sub-licensing. Enzymes such as Glucose oxidase-GOD , peroxidise-POD, Urease, cholesterol oxidase and cholesterol esterase : can enter these verticals.
2. R&D Equipments is a major problem, bio-equipment is a major opportunity area (No/very few people operate)…..Following areas they are interested in: Novel Rapid diagnostics technologies, markers,  Glucometer, Hb-meter, molecular diagnostics…..POCT .
3. Better, less expensive instrumentation technologies. Enzymes for biochemical tests. Rapid test technologies-list- pregnancy then HIV, HBV, tropinin, etc. (See website of Association of Diagnostic Manufacturers of India :www.admi.org).
4. Smart-phones: Android (google) based solutions for diagnostics…to ally with Elisa reader/spectrophotometer. MAbs for Diabetic markers (C-peptide, HA1C): CVD markers. Check with ATCC. Rapid test technologies. All hand held diagnostics
5. Its only through innovative technologies we can penetrate the market nationally and internationally and create a brand value for ourself. Like for example you see most of the products in diagnostics sectors are not stable above say 37 °C, if we have a products which are stable at even 45 °C and above then there is huge potential. Say insulin oral delivery  again has good potential market. Biosimilars stable at 40°C might sound good.

Medical devices:

1. Drug-delivery, elution kinetics. Novel alloys for stent systems, biocompatible material in stents. Also entering oncology drug delivery material. Stents in non-cardiac areas (peripheral stents). Self-expanding or shape memory stents.
2. Anything that optimizes/miniaturizes the controller components or iontophoresis. Sumatriptan succinate, GNRH, etc. Formulations for transdermal patch-friendly drugs.
3. Implant and fixator grade SS steel and titanium manufacture technologies. Forging of titanium and cobalt-chrome.
4. Hydroxy-apatite, ceramic and other biocompatible coatings for implants
5. Tech transfer of design.