DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-20 are pending and are under examination.
Specification
The disclosure is objected to because of the following informalities:
Appropriate correction is required.
The use of the term KEYTRUDA, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 2 is objected to because of the following informalities:
Please insert a space between “271” and “mM” in line 4.
Please provide the full meaning of “HWM” in line 8.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, 2, 15 and 16 recites the limitation “high molecular weight (HMW) species in liquid state". It is not clear what the species are. High molecular weight (HMW) species of what?
Claim 2 recites the limitation “HWM” in line 8. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chang Byeong Seon (“Chang”) CA 2951856 05/02/2013 in view of Sharma et al. WO 2018/204368 11/8/2018.
Claim 1: Chang et al disclose a pharmaceutical formulation (abstract), comprising: nivolumab (paragraph 87) which is an anti-PD-11 antibody and is also a pembrolizumab biosimilar (the instant specification at paragraph 49 discloses that “pembrolizumab” includes a pembrolizumab biosimilar);
5 mM to 25 mM L-glutamic acid (molecular weight of L -glutamic acid is 147g/mol) i.e. 3.4 mM (0.5 mg/mL) - 27.2 mM (4 mg/mL) or 6.8 mM (1 mg/mL) or 1.5 mg/mL (10 mM) or 2 mg/mL (13. 6 Mm) or 3 mg/mL (20 mM) or 4 mg/mL (27 mM) – paragraphs 80-81, 93, 94, 97-102, 106, 107, and 116;
L-threonine (molecular weight of L -threonine is 119 g/mol) 100 mM ( 12 mg/mL) to 300 mM (35 mg/mL (294 mM) or 36 mg/mL (302 mM) - paragraphs 80-81, 93, 94, 97-102, 106, 107, and 116; and
Polysorbate as surfactant (paragraph 122); and wherein the formulation is a liquid (paragraph 117, 125), has a pH in the range of 5.2-5.8 (paragraph 110).
Claim 2: Chang et al disclose a pharmaceutical formulation (abstract), comprising: nivolumab (paragraph 87) which is a pembrolizumab biosimilar (the instant specification at paragraph 49 discloses that “pembrolizumab” includes a pembrolizumab biosimilar);
10 mM (1 mg/mL) L-glutamic acid - paragraphs 80-81, 93, 94, 97-102, 106, 107, and 116 ;
Valine (molecular weight of valine is 117 g/mol) at 65 mM (7 mg/mL (59.5 mM) – 8 mg/mL (68 mM) or 271 mM ( 31 mg/mL (263 mM)- 32 mg/mL (272 mM) - paragraphs 80-81, 93, 94, 97-102, 106, 107, and 116; and
Polysorbate as surfactant (paragraph 122); and wherein the formulation is a liquid (paragraph 117, 125), has a pH in the range of 5.2-5.8 (paragraph 110).
Claim 3: Chang et al disclose the pharmaceutical formulation of claim 1, wherein the concentration of pembrolizumab biosimilar nivolumab is 25 to 200 mg/mL (Cheng et al disclose the protein of the stable protein formulation is at 25 mg/mL - 200 mg/mL at paragraph 113).
Claim 4: Chang et al disclose the pharmaceutical formulation of claim 1, wherein the concentration of pembrolizumab is 25 mg/mL – see paragraph 113.
Claim 5: Chang et al disclose the pharmaceutical formulation of claim 1, wherein the concentration of L-glutamic acid is 10 mM i.e. equivalent to 1.5 mg/mL at paragraph 116.
Claim 6: Chang et al disclose the pharmaceutical formulation of claim 1, wherein the concentration of L-threonine is 250 mM (about 30 mg/mL) or 271 mM (about 34 mg/mL). See paragraph 116.
Claim 9: Chang et al disclose the pharmaceutical formulation of claim 1, wherein the pH is 5.5. See paragraph 110.
Claim 10: Chang et al disclose the pharmaceutical formulation of claim 1, wherein the formulation does not comprise does not comprise histidine, sucrose or trehalose, or any combination thereof i.e. Chang et al disclose one or more excipients (see paragraph 122,124) and thus histidine, sucrose or trehalose, or any combination thereof can be excluded.
Claim 11: Chang et al disclose the pharmaceutical formulation of claim 1, wherein the formulation further comprises glycerol (paragraph 125).
Claim 12: Chang et al disclose the pharmaceutical formulation of claim 1, wherein the formulation does not comprise sucrose, sorbitol, glycerol, or trehalose, or any combination thereof. Chang et al disclose one or more excipients (see paragraph 122,124) and thus sucrose, sorbitol, glycerol, or trehalose, or any combination thereof can be excluded.
Claim 13: Chang et al does not disclose that pharmaceutical formulation comprises an antioxidant.
Claim 14: Chang et al at paragraph 79 disclose the pharmaceutical formulation of claim 1, wherein the formulation is suitable for intravenous administration.
Regarding claim 1 and claim 2 , Chang et al does not disclose 0.01 % w/v or 0.1% w/v polysorbate.
Regarding claim 7, Chang et al does not disclose the pharmaceutical formulation of claim 1, wherein the polysorbate is polysorbate 80.
Regarding claim 8, Chang et al does not disclose the pharmaceutical formulation of claim 1, wherein the amount of polysorbate is 0.02 % w/v or 0.07% w/v polysorbate 80.
Sharma et al disclose anti-PD1 antibody formulations that use polysorbate such as polysorbate 20 and polysorbate 80 as surfactant. Sharma et al disclose the amount of surfactant to be included in the anti-PD1 antibody formulations is an amount sufficient to perform the desired function, i.e. a minimal amount necessary to stabilize the active pharmaceutical ingredient (i.e. the anti-PD-1 antibody or antigen binding fragment thereof) in the formulation. Typically, the surfactant is present in a concentration of from about 0.008% to about 0.1% w/v% w/v (which overlaps with the claimed 0.01% to 0.1% w/v polysorbate).Sharma et al disclose the surfactant is present in the formulation in an amount from about 0.01% to about 0.04%; from about 0.01% to about 0.03%, from about 0.01% to about 0.02%, from about 0.015% to about 0.04%; from about 0.015% to about 0.03%, from about 0.015% to about 0.02%, from about 0.02% to about 0.04%, from about 0.02% to about 0.035%, or from about 0.02% to about 0.03%. In specific embodiments, the surfactant is present in an amount of about 0.02% or amount of about 0.01%, about 0.015%, about 0.025%, about 0.03%, about 0.035%, or about 0.04%. Sharma et al disclose the surfactants are typically added to formulations to provide stability, reduce and/or prevent aggregation or to prevent and/or inhibit protein damage during processing conditions such as purification, filtration, freeze-drying, transportation, storage, and delivery and is useful for providing additional stability to the active ingredient(s), i.e. the anti-PD-1 antibody' or antigen binding fragment thereof.
See page 4 lines 25-31, page 29 lines 16-38 and p. 31 lines 1-9.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have modified Chang et al such that the polysorbate is polysorbate 20 or polysorbate 80 at a concentrations disclosed by Sharma et al, for example at 0.008% to about 0.1% w/v% w/v (which overlaps with the claimed 0.01% to 0.1% w/v polysorbate) or 0.02% W/V, thus resulting in the instant invention with a reasonable expectation of success.
The motivation to do so is that Sharma et al disclose polysorbate in this concentration can be used as surfactant in a formulation comprising anti-PD-1 antibody.
The disclosure of the concentration of L-glutamic acid, L-threonine, L-valine and polysorbate concentrations renders the respective concentrations in the claims prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention.
Regarding claim 1, the combination of Chang and Sharma disclose the pharmaceutical formulation with the same components therefore, said pharmaceutical formulation has 0.2% or less high molecular weight (HMW) species in liquid state after being stored at 2°C to 8°C for 104 weeks as measured by size exclusion chromatography.
Regarding claim 2, the combination of Chang and Sharma disclose the pharmaceutical formulation with the same components therefore, said pharmaceutical formulation has 0.6% or less change in total amount of high molecular weight (HMW) species in liquid state after being stored at 2°C to 8°C for up to 6 months as compared to HWM at zero weeks, as measured by size exclusion chromatography.
Regarding claim 15, the combination of Chang and Sharma disclose the pharmaceutical formulation with the same components therefore, said pharmaceutical formulation has 0.1% or less change in total amount of HMW species in liquid state after being stored at 2°C to 8°C for 104 weeks as compared to HMW species at zero weeks as measured by size exclusion chromatography.
Regarding claim 16, the combination of Chang and Sharma disclose the pharmaceutical formulation with the same components therefore, said pharmaceutical formulation has 0.4% or less HMW species in liquid state after being stored at about 25°C for 24 weeks as measured by size exclusion chromatography.
Regarding claim 17-20:
Sharma further discloses that the anti-PD1 antibody can be administered to a subject to treat cancer in a subject, wherein the cancer is melanoma, lung cancer, head and neck cancer, bladder cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular cancer, lymphoma, renal cancer, mesothelioma, ovarian cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, salivary cancer, prostate cancer (e.g. hormone refractory prostate adenocarcinoma), pancreatic cancer, colon cancer, esophageal cancer, liver cancer, thyroid cancer, glioblastoma, glioma, and other neoplastic malignancies. Sharma further discloses the lung cancer in non-small cell lung cancer. Sharma further discloses the lung cancer is small-cell lung cancer. In some embodiments, the lymphoma is Hodgkin lymphoma. Sharma further discloses the lymphoma is non-Hodgkin lymphoma. In particular embodiments, the lymphoma is mediastinal large B-cell lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma (DLBCL). Sharma further discloses the breast cancer is triple negative breast cancer. Sharma further discloses the breast cancer is ER+/HER2- breast cancer. Sharma further discloses the bladder cancer is urothelial cancer. Sharma further discloses the head and neck cancer is nasopharyngeal cancer. Sharma further discloses the cancer is thyroid cancer. In other embodiments, the cancer is salivary cancer. Sharma further discloses the cancer is squamous cell carcinoma of the head and neck. Sharma further discloses the cancer is metastatic colorectal cancer with high levels of microsatellite instability (MSI-H). Sharma further discloses the cancer is a solid tumor with a high level of microsatellite instability (MSI-H). Sharma further discloses, the cancer is a solid tumor with a high mutational burden. Sharma further discloses the cancer is selected from the group consisting of: melanoma, non-small cell lung cancer, relapsed or refractory classical Hodgkin lymphoma, head and neck squamous cell carcinoma, urothelial cancer, esophageal cancer, gastric cancer, DLBCL and hepatocellular cancer. Sharma further discloses the cancer is a Heme malignancy. In certain embodiments, the Heme malignancy is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia- 1 protein (Mcl- 1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).
See under methods of use starting on page 40.
Sharma et al disclose the method further comprises administering pemetrexed which is a chemotherapeutic agent (p. 43 lines 1-6) or with other antibodies such as antibody to antibodies to VEGF, EGFR, Her2/neu, VEGF receptors, other growth factor receptors, CD20, CD40, CD-40L, OX-40, 4- 1BB, and ICOS), a growth inhibitory agent, an immunogenic agent (for example, attenuated cancerous cells, tumor antigens, antigen presenting cells such as dendritic cells pulsed with tumor derived antigen or nucleic acids, immune stimulating cytokines (for example, IL-2, lFNa2, GM-CSF), and cells transfected with genes encoding immune stimulating cytokines such as but not limited to GM-CSF). See p. 45 lines 15 -23.
Sharma et al disclose anti-PD1 antibody can be administered every 3 weeks or monthly and disclose a total weekly dose is generally at least 0.05 ug/kg, 0.2 ug/kg, 0.5 μg/kg, 1 μg/kg, 10 μg/kg, 100 μg/kg, 0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg body weight or more. See p. 46-47.
Regarding claims 17-20, it would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have further administered the pharmaceutical formulation of the combination of Chang and Sharma to a subject in order to treat cancer in said subject and further administer a chemotherapeutic as taught by Sharma et al, thus, resulting in the instant invention with a reasonable expectation of success. The motivation do so is that Sharma et al disclose anti-PD1 antibodies can be used to treat the various type of cancers listed above and that chemotherapy such as pemetrexed can also be administered as a second therapy.
Regarding claim 19, Sharma et al disclose anti-PD1 antibody can be administered every 3 weeks or monthly and disclose a total weekly dose is generally at least 0.05 ug/kg, 0.2 ug/kg, 0.5 μg/kg, 1 μg/kg, 10 μg/kg, 100 μg/kg, 0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg body weight or more and Sharma at page 46 lines 18-20 teach that determination of the appropriate dosage regimen may be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment.
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." See. MPEP 2144.05.
The general conditions of the dosage is disclosed and it would not have been inventive as of the effective filing date of the instant invention to discover the optimum or workable ranges by routine experimentation.
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chang Byeong Seon (“Chang”) CA 2951856 05/02/2013 and Sharma et al. WO 2018/204368 11/8/2018 as applied to claims 1 and 17 above, further in view of Kooshkaki et al. Int J Mol Sci. 2020 Jun 22;21(12):4427 (28 pages).
The combination of Chang and Sharma does not disclose the second therapy administered is ipilimumab.
Kooshkaki disclose that nivolumab can be administered with ipilimumab in the treatment of metastatic melanoma (table 1), renal cell carcinoma (table 2) and other cancers. See table such as breast, lung, esophageal etc. See whole paper.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have modified the method of Chang and Sharma as combined by administering ipilimumab as second therapeutic, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Kooshkaki disclose that nivolumab can be administered with ipilimumab in the treatment of cancer in order to improve outcomes (see Kooshkaki under conclusion).
Status of Claims
Claims 1-20 are rejected.
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/OLUWATOSIN A OGUNBIYI/Primary Examiner, Art Unit 1645
1 Kooshkaki et al. Int J Mol Sci. 2020 Jun 22;21(12):4427 at abstract.
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