Recent Trends in Pharma Cases: Patentable Subject Matter Under 101

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1 Recent Trends in Pharma Cases: Patentable Subject Matter Under 101 Hotel Hilton (Andheri East) Mumbai, India November 13-15, 2018 Hotel Taj Krishna Hyderabad, India November 12-14, 2018 Michael Dzwonczyk Sughrue Mion Sughrue Mion LLP All rights reserved

2 Subject Matter Eligibility Analysis Step 2A: is the claim is "directed to" judicial exceptions, i.e., an abstract idea, nature-based product, or natural phenomenon? Standard for Step 2A for nature-based product: does it have "markedly different characteristic"? structure, function, other properties Process claims are not subject to the markedly different characteristics analysis. Step 2B: does the claim as a whole add "Significantly more"?

3 Vanda Inc. v. West-Ward Pharms. (Fed. Cir. 2018) Vanda is an exclusive license to two patents, which are OB listed with regard to Fanapt Re 39,198 - directed to compounds (including iloperidone) 8,586,610 - directed to a method for treating schizophrenia patients with iloperidone wherein the dosage range is based on the patient's genotype based on finding that patient with poor metabolizing ability of CYP2D6 ("poor metabolizer") has a higher risk of QT2 prolongation caused cardiovascular symptoms the risk (side effects associated with QTc prolongation) can be reduced by lowering the dose of iloperidone

4 Vanda Inc. v. West-Ward Pharms. (Fed. Cir. 2018) Claim 1 of the '610 Patent. A method for treating a patient with iloperidone, wherein the patient is suffering from schizophrenia, the method comprising the steps of: determining whether the patient is a CYP2D6 poor metabolizer by: obtaining or having obtained a biological sample from the patient; and performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype; and if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount of 12 mg/day or less, and if the patient does not have a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day, wherein a risk of QTc prolongation for a patient having a CYP2D6 poor metabolizer genotype is lower following the internal administration of 12 mg/day or less than it would be if the iloperidone were administered in an amount of greater than 12 mg/day, up to 24 mg/day.

5 Vanda Inc. v. West-Ward Pharms. (Fed. Cir. 2018) D. Ct. : '198 claims infringed '610 method claims not invalid under sections 101, 103, 112 West-Ward was responsible for inducement infringement based on the proposed drug label For section 101, the D.Ct. decided that the treatment method was directed to a law of nature, but it had "significantly more" On Appeal: Only '610 patent decisions on validity and infringement were appealed

6 Vanda Inc. v. West-Ward Pharms. (Fed Cir 2018) West-Ward arguments - Claims are directed to natural relationship between iloperidone, CYP2D6 metabolism, and QT prolongation - Nothing inventive in the natural laws - Claims are indistinguishable from those held invalid in Myriad and Mayo Vanda arguments - DC erred in holding that the claims are directed to a law of nature - Claimed treatment method are patent eligible under the first analysis step as well as the second analysis step

7 Vanda Inc. v. West-Ward Pharms. (Fed Cir 2018) Fed Cir.: Vanda's claims are not directed to patent-ineligible subject matter Claim 1 requires specific steps determining the patient's CYP2D6 metabolizer genotype by obtaining a biological sample and performing a genotyping assay; and administering specific dose ranges of iloperidone depending on the patient's CYP2D6 genotype Unlike the claim in Mayo, the instant claims are directed to a novel method of treating a disease, not a diagnostic method based on relationships between metabolite concentrations and the likelihood that a drug would cause harm

8 Mayo, Claim 1, unpatentable A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising: (a) administering a drug providing 6-thioguanine to a subjechaving said immune-mediated gastrointestinal disorder; and (b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder, wherein the level of 6-thioguanine less than about 230 pmol per 8x108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and wherein the level of 6-thioguanine greater than about 400 pmol per 8x108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

9 Vanda Inc. v. West-Ward Pharms. (Fed. Cir. 2018) Claims reciting administration of a drug to a patient (Mayo) are different than claims reciting treatment of disease (Vanda) Inventors here recognized the relationship between iloperidone, CYP2D6 metabolism, and QTC prolongation, but claim the application of the drug to that relationship, not the relationship itself Claims require treating doctor to administer iloperidone in specific amounts depending on the result of the genotype assays Unlike Mayo, instant claims to not preempt a doctor s subsequent treatment decision Instant claims are directed to more than just an observation of a patient response Claims not directed to a natural relationship

10 Comparison of Vanda eligible claim v Mayo ineligible claim Vanda claim (Eligible) A method for treating a patient with iloperidone, wherein the patient is suffering from schizophrenia, the method comprising the steps of: determining whether the patient is a CYP2D6 poor metabolizer by: obtaining or having obtained a biological sample from the patient; and performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype; and if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount of 12 mg/day or less, and if the patient does not have a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day,.. Mayo Claim (Ineligible) A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising: (a) administering a drug providing 6- thioguanine to a subject having said immunemediated gastrointestinal disorder; and (b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder, wherein the level of 6-thioguanine less than about 230 pmol per 8x10 8 red blood cells indicates a need to increase the amount of said drug subsequently..

11 Rapid Litigation Management v Cellzdirect (Fed. Cir. 2016) 929 patent directed to an improved process for preserving hepatocytes by Subjecting previously frozen and thawed cells to density gradient fractionation Recovering viable cells from nonviable ones Refreezing viable cells The claims specify that the resulting hepatocyte preparation can be thawed and used immediately, exhibiting 70% viability after the second thaw 929 claimed process has significant benefits over prior processes

12 Rapid Litigation Management v Cellzdirect (Fed. Cir. 2016) Plaintiff sued Cellzdirect for infringement Cellzdirect sought summary judgment of invalidity under 101 D. Ct. granted the motion finding the 929 patent invalid Ø Step 1: 929 directed to an ineligible law of nature the discovery that hepatocytes are capable of surviving multiple freeze thaw cycles Ø Step 2: no inventive concept upon discovering capability of surviving multiple freeze-thaw cycles, the inventors simply reapplied a well understood freezing process

13 Rapid Litigation Management v Cellzdirect (Fed. Cir. 2016) Q: are the claims directed to a patent ineligible concept? Claims are not directed to the ability of hepatocytes to survive multiple freeze thaw cycles (natural law) Rather, claims directed to a new and useful laboratory technique for preserving hepatocytes Inventors may have discovered cells ability to survive multiple freeze thaw cycles, but that is not what they claimed Rather, claims directed to an application of that discovery Claims immediately distinguishable from those in Mayo and Alice

14 Rapid Litigation Management v Cellzdirect (Fed. Cir. 2016) The result of the 929 claims is not an observation or the detection of cells ability to survive freeze thaw cycles Rather, the result of the claims is a method of producing a desired preparation of cryopreserved hepatocytes Even under step two, the claimed improvement over existing technological process are sufficient to transform the process into an inventive application The claimed process for preserving hepatocytes for later use is a significant improvement over the prior art methods That the individual claim steps (freezing, thawing, and separating) were known in the art does not make the claim unpatentable

15 Rapid Litigation Management v Cellzdirect (Fed. Cir. 2016) Cellezdirect claim (Eligible) A method of producing a desired preparation of multi-cryopreserved hepatocytes, said hepatocytes being capable of being frozen and thawed at least two times, and in which greater than 70% of the hepatocytes of said preparation are viable after the final thaw, said method comprising: (A) subjecting hepatocytes that have been frozen and thawed to density gradient fractionation to separate viable hepatocytes from nonviable hepatocytes, (B) recovering the separated viable hepatocytes, and (C) cryopreserving the recovered viable hepatocytes to thereby form said desired preparation of hepatocytes without requiring a density gradient step after thawing the hepatocytes for the second time, wherein the hepatocytes are not plated between the first and second cryopreservations, and wherein greater than 70% of the hepatocytes of said preparation are viable after the final thaw. Mayo Claim (Ineligible) A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising: (a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and (b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder, wherein the level of 6-thioguanine less than about 230 pmol per 8x10 8 red blood cells indicates a need to increase the amount of said drug subsequently..

16 How does Cellzdirect method claim differ from Mayo claim? - The (Cellzdirect) claimed method is patent eligible because it applies the discovery that hepatocytes can be twice frozen to achieve a new and useful preservation process. - In examining claims under step two, we must view them as a whole, considering their elements both individually and as an ordered combination. - Here, the claimed process involves freezing and thawing hepatocytes twice. The individual steps of freezing all process claims that employ only independently known steps will be unpatentable. noting that the prior art taught away from multiple freezings, as [a] single round of freezing severely damages hepatocyte cells and results in lower cell viability. To require something more at step two would be to discount the human ingenuity that comes from applying a natural discovery in a way that achieves a new and useful end. 16

17 Rapid Litigation Management v Cellzdirect (Fed. Cir. 2016) Though a single freezing step was taught in the prior art, it was also well documented that cellular damage from a first freezing step resulted in a high percentage of nonviable cells Prior art taught away from multiple freezings Repeating a step that the prior art taught should be performed only once can hardly be considered routine or conventional Patent eligibility does not turn on ease of execution or obviousness of the application Summary judgment of invalidity vacated and remanded

18 Sequenom's '540 patent 1. A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample. Ariosa v. Sequenom (Fed. Cir. June, 2015)

19 Not enough more Sequenom sued Ariosa based on its Harmony Prenatal Test Ariosa argued claims were not patent-eligible under 101 D.Ct. agreed, held claims invalid: Fetal DNA in maternal plasma was a natural phenomenon DNA amplification techniques were well known Not enough "more" to make claims patentable Ariosa v. Sequenom (Fed. Cir. June, 2015)

20 Fed. Cir. Method begins with cffdna taken from a sample of maternal plasma (naturally occurring) Method ends with identification of paternally inherited cffdna None of the genetic information contained in the cffdna created or altered, so the claims are directed to matter that is naturally occurring. Ariosa v. Sequenom (Fed. Cir. June, 2015)

21 "significantly more" Need "significantly more" than a method of applying a natural law or phenomenon DNA amplification was conventional in 1997 '540 patent specification confirms the use of routine amplification procedures Court agrees that the claimed subject matter was a valuable scientific contribution, but not patentable Ariosa v. Sequenom (Fed. Cir. June, 2015)

22 A reluctant concurrence "It is hard to deny that Sequenom's invention is truly meritorious." "the new use of the previously discarded maternal plasma to achieve such an advantageous result is deserving of patent protection." "I see no reason, in policy or statute, why this breakthrough invention should be deemed patent ineligible." Ariosa v. Sequenom (Fed. Cir. June, 2015)

23 Opana ER (oxymorphone) Endo's '737 patent is directed to methods of using oxymorphone to treat pain in patients with renal impairment 1. A method of treating pain in a renally impaired patient, comprising the steps of: a. providing a solid oral controlled release dosage form, comprising: i. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and ii. a controlled release matrix; b. measuring a creatinine clearance rate of the patient and determining it to be (a) less than about 30 m[l]/min, (b) about 30 ml/min to about 50 ml/min, (c) about 51 ml/min to about 80 ml/min, or (d) above about 80 ml/min; and c. orally administering to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief; wherein after said administration to said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21 ng hr/ml. Endo v. Actavis (D. Del. 2015)

24 Opana ER (oxymorphone) Endo sued Actavis based on Actavis' ANDA for generic oxymorphone ER tablets Actavis alleged claims were patent ineligible under 101 and moved to dismiss Under 1 st step of Mayo, Defs argue '737 patent attempts to claim the natural law that the "bioavailability of oxymorphone is increased in people with impaired kidney function" Plaintiffs concede the 1 st step of Mayo, but urge that the claims are directed to a novel application of that discovery- the treatment of renally impaired patients Endo v. Actavis (D. Del. 2015)

25 Opana ER (oxymorphone) 737 patent states that oxymorphone is widely used for acute and chronic pain relief But the utilization of oxymorphone is not the invention The connection between the severity of renal impairment and the bioavailability of oxymorphone, which the '737 Patent sets forth in detail, is the subject matter of the invention Endo v. Actavis (D. Del. 2015)

26 Opana ER (oxymorphone) Claim 1 consists of three steps: (1) a "providing" step; (2) a measuring/determining" step; (3) and an "administering" step The "providing" step is insufficient to make the claim patentable simply informs patients and prescribing physicians of the relevant drug to be administered similar to the 'administering' step in Mayo because it merely identifies the specific drug for administration. The "measuring/determining" step "only instructs the physician to measure the patient's creatinine level to determine the level of renal impairment using a previously recognized method. Endo v. Actavis (D. Del. 2015)

27 Opana ER (oxymorphone) The "administering" step simply limits the relevant audience to patients and prescribing physicians, who treat chronic or acute pain with oxymorphone, and instruct patients on the administration of the correct dosage of oxymorphone depending on the severity of the renal impairment The steps in combination do not transform natural law into a patentable application of that law Inevitable that a doctor may infringe [claim 1 of the '737 patent] by checking a patient's creatinine level to determine renal impairment and lowering the dosage of oxymorphone in response to the lab test findings Complaint dismissed Endo v. Actavis (D. Del. 2015)

28 Athena v. Mayo (D. Mass. 2017) Athena s 820 is directed to the diagnosis of a form of myasthenia gravis, a chronic autoimmune disorder Claims are directed to a rapid method for diagnosing myasthenia gravis in which a radioactive label is attached to muscle specific tyrosinase kinase (MuSK) and then introduced to a sample of body fluid Radioactive label attached to MuSK forms 125 I-MuSK

29 Athena v. Mayo (D. Mass. 2017) Defendants argue the claims are directed to laws of nature: that the body fluid of some people with myasthenia gravis have autoantibodies to MuSK Plaintiffs argue the claims are directed to the use of a patent eligible molecule in an innovative and transformative manner that forms a specific complex with a modified version of MuSK ( 125 I-MuSK ) Plaintiffs argue that because I-MuSK is not naturally occurring, the claim is patent eligible under 101

30 Athena v. Mayo (D. Mass. 2017) Court: While 125 I-MuSK and antibody/musk complexes are not found in nature, this does not transform the claims to a patent eligible concept Claims are not directed to the creation of man-made complexes, but rather, to methods for diagnosis of the disease Claims are directed to the interaction of 125 I-MuSK and body fluid, an interaction which is naturally occurring

31 Athena v. Mayo (D. Mass. 2017) The purpose of the patent is to detect whether any antibody antigen complexes are formed between the 125 I-MuSK receptor and the antibodies present in said body fluid Because patent focuses on this natural occurrence, is directed to ineligible subject matter Claims similar to those invalidated by the Supreme Court in Mayo Claims are not transformed to eligible subject matter simply by recitation of the use of the man-made molecule Sole purpose of claims is to diagnose myasthenia gravis

32 Athena v. Mayo (D. Mass. 2017) Step 2: something more? Defendants argue claimed method uses well-known techniques for identifying the presence of autoantibodies to MuSK Plaintiffs urge that detecting autoantibodies was neither well understood nor routine Court disagrees with plaintiffs none of the complexity argued by plaintiffs is described or claimed in the patent To the contrary, the patent states that the suitable label is 125 I or the like, and that iodination of the label is a standard technique in the art

33 Athena v. Mayo (D. Mass. 2017) Step 2: something more? Court rejects argument that the use of the man-made molecule necessarily makes the claims patent eligible Claims as a whole are directed to diagnosing neurotransmission or developmental disorders, not to a process for creating 125 I-MuSK Claims held invalid under 101

34 Keytruda (pembrolizumab) BMS 994 patent directed to method for treating metastatic melanoma through the IV administration of humanized anti- PD-1 monoclonal antibody BMS charges Merck with infringement based on its sales of Keytruda Merck moved to dismiss, arguing the 994 patent claims are directed to ineligible subject matter BMS v. Merck (D. Del. 2016)

35 Keytruda (pembrolizumab) Merck alleges the claims are directed to the natural phenomenon of the bodies mechanism for regulating the immune system No inventive contribution beyond the natural phenomenon itself BMS states that the method of treatment claims rely on the human body s ability to respond to the disease BMS also argues that every method of therapeutic treatment at its basic level relies on the biological activity of the patient s immune system But the claims add this step of administering a composition of anti- PD-1 antibodies to induce an immune response that would not otherwise occur in the patient s natural state BMS v. Merck (D. Del. 2016)

36 Keytruda (pembrolizumab) Court: Claims rely on the scientific fact that blocking activation of the PD 1 pathway enables the patient's T cells to perform their normal biological activity of removing cancer cells. By preventing PD 1 ligands from binding to the PD 1 receptor, the anti PD 1 antibodies prevent the PD 1 pathway from suppressing the immune system, which, in turn, kills and clears the body of the cancer cells This is interaction is a natural phenomenon Not enough facts to determine whether claims recite something more (Mayo step two) to make them patentable BMS v. Merck (D. Del. 2016)

37 Keytruda (pembrolizumab) At the pleading stage, 994 patent entitled to a presumption of validity Not clear and convincing evidence that ineligibility is the only plausible reading of the patent Motion to dismiss denied BMS v. Merck (D. Del. 2016)

38 !फर %मल(ग. Thank you.