Monthly Archives: August 2017

United States district court upholds the validity of two Horizon Pharma patents covering VIMOVO®

Horizon Pharma plc, an Irish specialty biopharmaceutical company, on 27 June 2017, reported that the United States district court for the district of New Jersey upheld the validity of two Horizon Pharma patents covering VIMOVO®, a pain relief treatment for arthritis patients, and that the ANDA applicants viz. Lupin Limited, Dr. Reddy’s Laboratories and Mylan Inc. would infringe at least one of the two patents with their proposed generic version of VIMOVO®.

What is VIMOVO®?

            VIMOVO® is a fixed dose combination of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), and esomeprazole magnesium, a proton pump inhibitor (PPI). VIMOVO is used to relieve signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing stomach (gastric) ulcers in people who are at risk of developing gastric ulcers with NSAIDs.

            The two Horizon Pharma patents which cover VIMOVO® and have now been upheld as valid by the US district court are:

  1. US6926907B2 – expires in February 2023. The US’907 patent claims a pharmaceutical composition in unit dosage form comprising therapeutically effective amounts of an acid inhibitor and a non-steroidal anti-inflammatory drug (NSAID), which unit dosage form provides for coordinated release of the acid inhibitor and the NSAID.
  2. US8557285B2 – expires in May 2022. The US’285 patent claims a pharmaceutical composition in unit dosage form comprising therapeutically effective amounts of: (a) esomeprazole, wherein at least a portion of said esomeprazole is not surrounded by an enteric coating; and (b) naproxen surrounded by a coating that inhibits its release from said unit dosage form unless said dosage form is in a medium with a pH of 3.5 or higher; wherein said unit dosage form provides for release of said esomeprazole such that upon introduction of said unit dosage form into a medium, at least a portion of said esomeprazole is released regardless of the pH of the medium.

            On April 21, 2011, July 25, 2011, and June 28, 2013, Horizon Pharma filed patent infringement lawsuits at the New Jersey District Court against Lupin Limited, Dr. Reddy’s Laboratories and Mylan Inc., seeking adjudication for patent infringement by these companies of one or more claims of the US‘907 and US’285 Patents. The infringement lawsuit came after these companies filed an Abbreviated New Drug Application (“ANDA”) with the U.S. Food and Drug Administration (FDA) seeking regulatory approval to market a generic version of VIMOVO before the expiration of the US‘907 patent in February 2023 and the US’285 patent in May 2022. At trial, the ANDA applicants alleged that the claims of the US‘907 and US’285 patents, listed in the Orange Book for VIMOVO were invalid.

            The announcement from Horizon Pharma came on the same day the U.S. district court for the district of New Jersey ruled in favor of Horizon Pharma and upheld the validity and enforceability of the patents at issue. Horizon Pharma says the outcome of the infringement lawsuit will prevent the launch of generic VIMOVO, which is being developed by Indian drug makers Lupin Limited and Dr. Reddy’s Laboratories as well as American generic drug maker Mylan Inc., in the United States.

TAKEDA PHARMACEUTICAL’S PATENT ON CANCER DRUG VELCADE® UPHELD BY THE US COURT OF APPEALS FOR THE FEDERAL CIRCUIT

On July 17, 2017, the United States Court of Appeals for the Federal Circuit ruled that the U.S. Patent No. 6,713,446 (“the ‘446 patent”) covering Takeda Pharmaceutical’s cancer drug Velcade® is valid and enforceable. The appellate court decision overturned an earlier 2015 decision from a US District Court which ruled the ‘446 patent was invalid as the compound it covered was the result of an obvious process. The lawsuit came on the heels of ANDA submissions by generic companies, including Sandoz Inc, Accord Healthcare Inc, and Actavis LLC, to the FDA for a generic version of Velcade® prior to the expiration of the ‘446 patent in 2022.

VELCADE®:

Velcade® (bortezomib) is approved for the treatment of people with multiple myeloma (a cancer of the plasma cells). Velcade® is also approved for the treatment of people with mantle cell lymphoma (a cancer of the lymph nodes). The drug generated U.S. sales of $1.13 billion in 2016.

In 2003, the Food and Drug Administration (“FDA”) granted “accelerated approval” to New Drug Application No. 21-602 for VELCADE® for Injection, for the treatment by intravenous administration of patients with multiple myeloma who have received at least two prior therapies and have demonstrated disease progression on the last therapy. VELCADE® for Injection was subsequently approved in 2005 for treatment by intravenous administration of patients with multiple myeloma who had received at least one prior therapy; in 2006 for treatment by intravenous administration of patients with mantle cell lymphoma who had failed at least one prior therapy; in 2008 for frontline treatment by intravenous administration of patients with multiple myeloma; in 2012 for subcutaneous administration; and in 2014 for treatment of adult patients with multiple myeloma who had previously responded to VELCADE® for Injection therapy and relapsed at least six months following completion of prior VELCADE® for Injection treatment.

The ‘446 patent has been listed in connection with VELCADE® for Injection in the FDA’s Orange Book.

 

US District Court ruling related to VELCADE® patent:

On August 2, 2012, November 19, 2012, and December 21, 2012, Millennium Pharmaceuticals Inc filed patent infringement lawsuits in the United States District Court for the Delaware against Sandoz Inc, Accord Healthcare Inc, and Actavis LLC (collectively, “defendants”) respectively, alleging that the ANDA applications filed by the defendants infringe on claims 20, 31, 49, and 53 of the ‘446 patent. The defendants argued, and the District Court agreed, that asserted claims 20, 31, 49, and 53 of the ‘446 Patent were invalid as obvious.

Millennium Pharmaceuticals Inc, the Takeda Oncology Company, is the exclusive licensee of the ‘446 patent which covers a D-mannitol ester of bortezomib, the active ingredient in Velcade®. This active ingredient is claimed in claim 20 of the ‘446 patent:

[Claim 20] The lyophilized compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

Claims 31, 49, and 53 of the ‘446 patent recite method of preparing the D-mannitol ester of bortezomib via lyophilization, a lyophilized cake comprising the D-mannitol ester of bortezomib, and reconstitution of the lyophilized mixture with a pharmaceutically acceptable carrier, respectively.

[Claim 31] The method of claim 23, wherein the compound of formula (1) is D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

[Claim 49] A lyophilized cake comprising the compound of claim 20.

[Claim 53] The method of claim 31 further comprising (c) reconstituting the lyophilized mixture with a pharmaceutically-acceptable carrier.

Bortezomib and its esters were already described and claimed in U.S. Patent No. 5,780,454 (“the ‘454 patent”). The ‘454 patent also identified bortezomib as a very potent, promising lead candidate with the highest in-vivo activity of all the compounds disclosed in the ‘454 patent. The ‘454 patent was considered as the closest prior art document by the defendants as well as the district court.

At trial, the defendants predominately argued that the asserted claims were obvious because the ‘446 patent claims the inherent result of an obvious process-namely, that freeze-drying bortezomib with mannitol produces an ester. Specifically, the defendants argued that lyophilization is a standard formulation option and that one skilled in the art would have chosen lyophilization process in order to stabilize bortezomib. In response, Millennium Pharmaceuticals argued that a person of ordinary skill would avoid lyophilization in developing a formulation involving bortezomib because bortezomib was known to be unstable even in the dry state as a freestanding solid compound. Millennium Pharmaceuticals also argued that a person of ordinary skill would not have expected a lyophilized mannitol ester of bortezomib to provide dramatic improvements in stability, solubility and dissolution as compared to bortezomib. The district court however agreed with the defendants that lyophilization was well-known in the field of formulation and often utilized when a liquid formulation provided limited success, and that the decision to attempt a lyophilized formulation of bortezomib was routine application of a well-known problem-solving strategy. The district court also concluded that mannitol was among the “finite number of identified, predictable solutions” to freeze-drying investigational anti-cancer drugs like bortezomib, and one skilled in the art would have found it obvious to choose mannitol for the lyophilization process. As such, the asserted claims of the ‘446 patent were found invalid under 35 U.S.C. § 103.

 

US Appeals Court reverses the District Court’s obviousness determination:

The US Court of Appeals for the Federal Circuit first analyzed the District Court’s obviousness determination by framing the relevant question as whether a person of ordinary skill, seeking to remedy the known instability and insolubility and to produce an efficacious formulation of bortezomib, would obviously produce the claimed and previously unknown D-mannitol ester of bortezomib. In its analysis, the Federal Circuit found error in the District Court’s obviousness determination because (1) there is no teaching or suggestion in the prior art references to produce the claimed mannitol ester, (2) no reference or combination of references provide a reason to make the claimed mannitol ester of bortezomib, and (3) no reference shows or suggests ester formation at freeze-drying conditions, or that any such ester might solve the problems of instability and insolubility of the free acid while dissociating rapidly in the bloodstream.

The Federal Circuit agreed with the defendants that lyophilization was generally known in formulating pharmaceutical products, bulking agents were known for use in lyophilization, and mannitol was a known bulking agent. However, the Federal Circuit explained that for the compound to be obvious, the prior art must teach or suggest that lyophilization of bortezomib in the presence of mannitol would produce a chemical reaction and form a new chemical compound (i.e. mannitol ester of bortezomib), or provide a reason to make this specific new chemical compound, or describe that this new compound would solve the previously intractable problems of bortezomib formulation. The Federal Circuit also stated that “[a]lthough mannitol was a known bulking agent, and lyophilization was a known method of drug formulation, nothing on the record teaches or suggests that a person of ordinary skill should have used mannitol as part of a synthetic reaction to make an ester through lyophilization.”

With regard to the District Court’s conclusion concerning the unexpected results and commercial success of the lyophilized mannitol ester of bortezomib, the Federal Circuit made the following ruling:

“We conclude that the district court should have treated bortezomib as the closest prior art compound, and acknowledged the unrebutted evidence that the D-mannitol ester of bortezomib exhibited unexpected results compared with bortezomib, including unexpectedly superior stability, solubility, and dissolution.”

 

“The district court clearly erred in attributing Velcade®’s commercial success to bortezomib alone, as bortezomib is not a viable commercial product and had been denied FDA approval because of its instability. The D-mannitol ester was responsible for Velcade®’s successful results, for the D-mannitol ester is necessary to provide the required solubility and stability.”

Accordingly, the Federal Circuit reversed the District Court’s ruling that the asserted claims of the ‘446 patent are invalid due to obviousness. The appellate court’s ruling will help Takeda to put off the risk of generic competition until the ‘446 patent expires in 2

Compulsory licensing

Compulsory licenses are sovereign state authorizations which enable a third party to make, use, or sell a patented product without the consent of the patent holder. Provisions pertaining to compulsory licensing are provided for under both the Indian Patent Act, 1970, as well as the international legal agreement between all the member nations of WTO – the TRIPS. In India, Chapter XVI of the Indian Patent Act, 1970 deals with compulsory licensing while the conditions which need to be fulfilled for the grant of a compulsory license are laid down under Sections 84 and 92 of the Act.

In accordance with Section 84(1) of the Indian Patent Act, 1970, after three years from the grant of a patent, any interested person may make an application for a compulsory license on the grounds that the patented invention:

(a) Does not satisfy the reasonable requirements of the public;

(b) Is not available to the public at a reasonably affordable price; and

(c) Is not worked in the territory of India.

In addition to the aforementioned grounds, according to Section 92 of the Act, compulsory licenses can also be issued suo motu by the Controller of Patents pursuant to a notification issued by the Central Government if there is either a “national emergency” or “extreme urgency” or in cases of “public non-commercial use”. The said section enables the Government of India to notify to the public of such extreme circumstances, whereupon, any person interested can apply for a compulsory license and the Controller in such case may grant to the applicant a license over the patent on such terms and conditions as he thinks fit.

The patentee, however, has the right to be heard in the compulsory licensing application process.

India’s first ever compulsory license was granted by the Patent Office on March 9, 2012, to Hyderabad-based Natco Pharma for the production of generic version of Bayer’s Nexavar, an anti-cancer agent used in the treatment of liver and kidney cancer. It was established in the Bayer vs Natco case that only 2% of the cancer patient population had an easy access to the drug and that the drug was being sold by Bayer at an exorbitant price of 2.8 lakh INR for a month’s treatment[1]. Further, on the ground that Nexavar was being imported within the territory of India, the Indian Patent Office issued a compulsory license to Natco Pharma, which assured that the tablets would be sold for Rs. 8,880/- per month. It was settled that 6% of the net sales of the drug would be paid to Bayer by Natco Pharma as royalty.

In the second case of Compulsory licensing in India, the Controller rejected BDR Pharmaceuticals’ application for compulsory license (made on March 4, 2013) for BMS cancer drug, SPRYCEL[2]. The Controller rejected the compulsory license application made by BDR for stating that BDR has failed to make prima facie case for the making of an order under section 87 of the Act. Controller in the said case observed that BDR Pharmaceuticals had not made any credible attempt to procure a voluntary license from the Patent holder and the applicant has also not acquired the ability to work the invention to the public advantage.

In the most recent case of compulsory licensing in India, Lee Pharma, a Hyderabad based Indian pharma company, filed an application for compulsory license (dated 29.06.2015) for the patent covering AstraZeneca’s diabetes management drug Saxagliptin. In order to make a prima facie case, Lee Pharma strived to show that their negotiations for a voluntary license with the patent owner were not rewarding as they did not receive any response from the Patent owner within a reasonable period. The grounds alleged by Lee Pharma were that:

  • the patentee has failed to meet the reasonable requirements of the public,
  • the patented invention is not available to the public at a reasonably affordable price, and
  • the patented invention is not worked in India.

However, all the three grounds of Lee Pharma were rejected by the Controller General and the Compulsory license application was refused[3]. The application was rejected on the basis that Lee Pharma failed to demonstrate what the reasonable requirement of the public was with respect to Saxagliptin and further failed to demonstrate the comparative requirement of the drug Saxagliptin vis-a-vis other drugs which are also DPP-4 inhibitors. Further, Controller General held that all the DPP-4 inhibitors were in the same price bracket and the allegation that Saxagliptin alone was being sold at an unaffordable price was unjustified. The Controller General also stated that Lee Pharma failed to show the exact number of patients being prescribed the patented drug and how many of them were unable to obtain it due to its non-availability and consequently it was difficult to hold whether manufacturing in India was necessary or not.

Considering the last two compulsory license cases in India, it is clear that the provisions of compulsory license cannot be misemployed to diminish the rights of the patent holders and that the basic jurisprudence governing the subject of compulsory license lies in balancing the conflicting interest of the patentee’s exclusive rights and making the invention available at an affordable price to third parties in case of need.

About the author: Tanu Goyal, Patent Associate at IIPRD and can be reached at: tanu@khuranaandkhurana.com

[1] http://thefirm.moneycontrol.com/story_page.php?autono=1132015

[2]https://iiprd.wordpress.com/2013/11/13/indian-patent-office-rejects-compulsory-licensing-application-bdr-pharmaceuticals-pvt-ltd-vs-bristol-myers-squibb/

[3] http://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/india-rejects-compulsory-license-application-of-lee-pharma-against-astrazenecas-saxagliptin/articleshow/50652935.cms