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 .
DETAILED ACTION
Claims 1-4, 6, 34, 39-40, 42, 46-49, 51, 57-60, 62, and 68-83 are pending.
Specification/Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the abstract recites “e.g.”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 6, 34, 39-40, 42, 46-49, 51, 57-60, 62, and 68-83 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a method for treating cancer in a human subject in need thereof, the method comprising administering to the subject at least two of: (i) about 375-500 mg of an anti-PD-1 active agent once every three weeks or four weeks; (ii) about 400-1000 mg of an anti-TIM-3 active agent once every two weeks, three weeks, or four weeks; and (iii) about 350-750 mg of an anti-LAG-3 active agent once every two weeks, three weeks, or four weeks. Thus, the claims are drawn to the method for treating cancer comprising administering any anti-PD-1 active agent, any anti-TIM-3 active agent, and any anti-LAG-3 agent. No example or structure of the agents are recited.
With regards to the agents, the instant specification discloses the following:
Paragraphs are from the published specification
[0035]
In certain embodiments, the active agents of the present disclosure (e.g., anti-PD-1 active agent, anti-TIM-3 active agent, anti-LAG-3 active agent) comprise an antigen binding protein, such as an antibody or an antigen binding—fragment of an antibody. In certain embodiments, the active agents of the present disclosure (e.g., anti-PD-1 active agent, anti-TIM-3 active agent, anti-LAG-3 active agent) comprise an antibody or an antigen binding-fragment of an antibody.
Anti-PD-1 active agent:
[0047]
In certain embodiments, the methods, combination therapies, uses, or kits of the present disclosure comprise an anti-PD-1 active agent. In certain embodiments, the anti-PD-1 active agent comprises an anti-PD-1 antibody, or PD-1 binding-fragment thereof.
[0051]
In certain embodiments, the anti-PD-1 antibody is nivolumab, also known as BMS-936558 or MDX1106 (Bristol-Myers Squibb). In certain embodiments, the anti-PD-1 antibody is pembrolizumab, also known as lambrolizumab or MK-3475 (Merck & Co). In certain embodiments, the anti-PD-1 antibody is pidilizumab, also known as CT-011 (CureTech). In certain embodiments, the anti-PD-1 antibody is MEDI0680, also known as AMP-514 (Medimmune). In certain embodiments, the anti-PD-1 antibody is PDR001 (Novartis). In certain embodiments, the anti-PD-1 antibody is REGN2810 (Regeneron). In certain embodiments, the anti-PD-1 antibody is PF-06801591 (Pfizer). In certain embodiments, the anti-PD-1 antibody is BGB-A317 (BeiGene). In certain embodiments, the anti-PD-1 antibody is TSR-042 (AnaptysBio). In certain embodiments, the anti-PD-1 antibody is SHR-1210 (Hengrui).
The instant specification discloses the that PD-1 active agent comprises an anti-PD-1 antibody comprising (i) a Heavy Chain Variable Domain (VH), comprising a CDRH1 Domain, a CDRH2 Domain, and a CDRH3 Domain: SEQ ID Nos: 1-2-3, respectively, and (ii) a Light Chain Variable Domain (VL), comprising a CDRL1 Domain, a CDRL2 Domain, and a CDRL3 Domain, comprising SEQ ID Nos: 4-5-6, respectively.
T-cell Immunoglobulin and Mucin Domain-3 (TIM3) Active Agent:
[0078]
In certain embodiments, the methods, combination therapies, uses, or kits of the present disclosure comprise an anti-TIM-3 active agent. In certain embodiments, the anti-TIM-3 active agent comprises an anti-TIM-3 antibody, or TIM-3 binding-fragment thereof.
The instant specification discloses that the TIM-3 active agent comprises an anti-TIM-3 antibody comprising (i) a Heavy Chain Variable Domain (VH), comprising a CDRH1 Domain (seq id no: 11 OR 46), a CDRH2 Domain (seq id no 12), and a CDRH3 Domain: (SEQ ID NO: 13), and (ii) a Light Chain Variable Domain (VL), comprising a CDRL1 Domain (SEQ ID NO 47, 48, or 14), a CDRL2 Domain (SEQ ID NO: 50, 15, OR 51, and a CDRL3 Domain (52, 16 or 53)
Lymphocyte Activation Gene 3 (LAG-3) Active Agent:
The instant specification discloses that the LAG-3 active agent comprises an anti-LAG3 antibody comprising (i) a Heavy Chain Variable Domain (VH), comprising a CDRH1 Domain, a CDRH2 Domain, and a CDRH3 Domain, comprising SEQ ID Nos: 21, 22, and 55 OR 23, respectively, and (ii) a Light Chain Variable Domain (VL), comprising a CDRL1 Domain, a CDRL2 Domain, and a CDRL3 Domain, comprising SEQ ID Nos: 24, 25, and 26.
Other than the examples cited above, the instant specification does not disclose any other examples of anti-PD-1, anti-TIM-3, or anti-LAG3 antibodies or compounds.
Regarding anti-PD-1 agents: The use of anti-PD-1 and anti-PD-L1 antibodies are known in the art as taught by Sunshine et al (2015; Current opinion in pharmacology, vol 23, 2015, pgs 32-38) and supported in the instant specification. However, Surmiak et al (Int. J. Mol. Sci. 2021, 22(21), 11797) teaches that targeting PD-1 with small molecules is considered much more difficult to achieve compared to antibodies targeting PD-1 or PD-L1. [pg 1, 2nd paragraph] Surmiak teaches that although there are new ideas of small molecules, there has only been moderate improvement of the bioactivity of these molecules that could be achieved, and that the activities of these drug candidates are far lower than the therapeutic antibodies. [pg 7, Discussion] Thus, the art and the specification do not provide support for the broad genus of any immune checkpoint inhibitor.
Regarding TIM-3 agents and anti-LAG-3 agents: Ngoiw et al (Prospects for TIM3-Targeted Antitumor Immunotherapy. Cancer Res. 2011 Nov 1;71(21):6567-71) teaches that there are few studies that have extensively assess the mechanism of action of anti-TIM3 agents against tumors. [whole document] Lu et al (Promising immunotherapy targets: TIM3, LAG3, and TIGIT joined the party. Mol Ther Oncol. 2024 Feb 12;32(1):200773) teaches that immune checkpoint inhibitors have shown promising immunotherapy for restoring T cell function and reactivating antitumor immunity. Lu teaches that there are ongoing studies to evaluate the next generation of immune checkpoint inhibitors, including LAG3 and TIM3. Thus, although there are some ongoing studies with these agents, the art and the specification does not provide support for the broad genus of any TIM-3 and/or LAG-3 agents.
To provide adequate written description and evidence of possession of the claimed composition agent genus, the instant specification can structurally describe representative structures, antibodies, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for structures and/or antibodies that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future agents, including antibodies, yet to be discovered that may function as claimed.
Given the lack of representative examples to support the full scope of the claimed genus of the anti-PD-1 active agents, anti-TIM3 active agents, and anti-LAG-3 active agents, and lack of reasonable structure-function correlation with regards to any compounds that function as claimed, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner’s Suggestion: Amend claim 1 to include the exact structure/sequence of the anti-PD-1, anti-TIM-3 and anti-LAG-3 active agents. That is, amend claim 1 to include the limitations of claims 39, 48, or 59, or to include the sequences of the heavy chain variable domains and light chain variable domains.
PARTIAL STRUCTURE:
Dependent claim 40 recites: The method of claim 39, wherein the Heavy Chain Variable Domain of the anti-PD-1 antibody or fragment thereof comprises an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 7 , and wherein the Light Chain Variable Domain of the anti-PD-1 antibody or fragment thereof comprises an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 8.
Dependent claim 42 recites: The method of claim 39, wherein the anti-PD-1 antibody or fragment thereof comprises a Heavy Chain (HC) sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to: SEQ ID NO: 9, and
wherein the anti-PD-1 antibody or fragment thereof comprises a Light Chain (LC) sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to: SEQ ID NO: 10.
Dependent claim 48 recites: The method of claim 48, wherein the Heavy Chain Variable Domain of the anti-TIM-3 antibody or fragment thereof comprises an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 17, and wherein the Light Chain Variable Domain of the anti-TIM-3 antibody or fragment thereof comprises an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 18
Dependent claim 51 recites: The method of claim 48, wherein the anti-TIM-3 antibody or fragment thereof comprises a Heavy Chain (HC) sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 19 and wherein the anti-TIM-3 antibody or fragment thereof comprises a Light Chain (LC) sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 29.
Dependent claim 60 recites: The method of claim 59, wherein the Heavy Chain Variable Domain of the anti-LAG-3 antibody or fragment thereof comprises an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 27, and wherein the Light Chain Variable Domain of the anti-LAG-3 antibody or fragment thereof comprises an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 28.
Dependent claim 62 recites: The method of claim 59, wherein the anti-LAG-3 antibody or fragment thereof comprises a Heavy Chain (HC) sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 29, and wherein the anti-LAG-3 antibody or fragment thereof comprises a Light Chain (LC) sequence which is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 30.
Thus, the claims recite only a partial structure of the anti-PD-1, anti-TIM3, or anti-LAG3 antibodies, comprising up to 25% sequence discrepancy. The instant specification does not disclose any representative variants of the antibodies that comprise less than 100% SEQ ID NOS that function to bind to either, PD-1, TIM3 or LAG3.
It is well known in the art that that changes in amino acid structures, particularly in CDR regions, can have impacts on antigen binding that are unpredictable. Rabia et al (Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility. Biochemical engineering journal, 137, 365–374, 2018) and Vajdos et al (Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis. Journal of molecular biology, 320(2), 415–428, 2022) teaches that changes to CDRs are unpredictable in terms of affinity, specificity, and solubility, (see Rabia whole documents), and teaches that even minute changes to the CDR region can impact binding affinities. (see Figure 2, effects of CDR mutations on binding affinity), respectively. Rudikoff et al (Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1979-83) teaches that single amino acid substitutions alter antigen-binding specificity. [Abstract] Lastly, Herold et al (Sci Rep. 2017 Sep 25;7(1):12276) teaches and demonstrates that single and double mutations in exemplary antibodies, and found that single point mutations in the VH region can completely abolish antigen binding. [see pg 8]
To provide adequate written description and evidence of possession of the claimed antibodies comprising the instantly claimed sequences, the instant specification can structurally describe representative antibodies, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
Applicants have not established any reasonable structure-function correlation with regards to the sequences of the antibodies that can be altered and still maintain function. Therefore, one could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the antibodies, and lack of reasonable structure-function correlation with regards to the unknown variant sequences that can be altered and still maintain binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of the vast genus of sequence variant antibodies, that is required to practice the claimed inventions.
Claims 1-4, 6, 34, 39-40, 42, 46-49, 51, 57-60, 62, and 68-83 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of cancer comprising administering combination of an anti-PD-1 antibody, an anti-TIM-3 antibody and an anti-LAG-3 antibody, does not reasonably provide enablement for at least two of the agents and any agent. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
BREADTH OF THE CLAIMS: The claims are drawn to a method for treating cancer in a human subject in need thereof, the method comprising administering to the subject at least two of: (i) about 375-500 mg of an anti-PD-1 active agent once every three weeks or four weeks; (ii) about 400-1000 mg of an anti-TIM-3 active agent once every two weeks, three weeks, or four weeks; and (iii) about 350-750 mg of an anti-LAG-3 active agent once every two weeks, three weeks, or four weeks. Thus, the claims are drawn to the use of any anti-PD-1 active agent, any anti-TIM3 agent, and any anti-LAG-3 agent. Also, the claim recites at least two of the agents, thus it can be any combination of: anti-PD-1 agent + anti-TIM3 agent, anti PD-1 agent and an anti-LAG-3 agent, and anti TIM-3 agent and an anti-LAG-3 agent.
STATE OF THE ART: It is well known that the art of anti-cancer therapy is highly unpredictable. Lopez et al (Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat Rev Clin Oncol. 2017;14(1):57-66) teaches that the challenges include finding the best combination to explore and that the scale of biological complexity of the mechanisms of resistance to targeted treatment is large and requires several novel approaches. Lopez also teaches that there are hundreds of targeted treatments and the number of combinations trials outweigh the number of patients who can be entered into trials to evaluate them. Lopez also teaches that combination therapy in clinic results into issues including toxicity, pharmacokinetic interactions and finding the correct timing and context of using these combinations [pg 3, 2nd paragraph] Furthermore, Gura (Science, 1997, 278:1041-1042) teaches that researchers face the problem of sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile and teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models that only 29 have actually been shown to be useful for chemotherapy See p. 1041, see 1st and 2nd para. Furthermore, Kaiser (Science, 2006, 313: 1370) teaches that 90% of tumor drugs fail in patients. See 3rd col., 2nd to last para. Chames et al (British J. of Pharmacology, 2009, 157, 220-233) teach that there are several challenges to development therapeutic antibodies. These challenges include functional limitations such as inadequate pharmacokinetics, tissue accessibility and impaired interactions with the immune system (Abstract). Additionally, Chames teaches several limitations of therapeutic antibodies such as affinity between the antibody and its antigen, competition with patient’s IgG, and efficiency issues in triggering the immune response (pages 224-225). More specifically, de Miguel M et al (Clinical Challenges of Immune Checkpoint Inhibitors. Cancer Cell. 2020 Sep 14;38(3):326-333) teaches that there are many clinical challenges surrounding immune checkpoint inhibitors, including toxicity and efficacy. [whole document] Thus, it is unpredictable to claim that any immune checkpoint inhibitor would work in combination as instantly claimed.
PREDICTABILITY: Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that administration of an any two antibodies can be combined and treat cancer as claimed.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine which combination is administered to treat cancer, as claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining exactly which combinations can be combined, and is not routine in the art as these diseases are unrelated and comprise various subgroups within each disease state. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
Claim 79 is 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.
Regarding claim 79, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d)
Claims 1-4, 6, 34, 39-40, 42, 46-49, 51, 57-60, 62, and 68-83 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.
The term “about” in claim 1 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-4, 6, 34, 58, 70-71, 75, and 80-83 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Stein et al (US20200223924 A1; published 7/16/2020).
Stein teaches a method for treating cancer in a human subject, the method comprising administering to the subject an anti-PD-1 antibody, an anti-TIM-3 antibody, and an anti-LAG-3 antibody. [0075, 0083-0085, 0124, 0128] Stein teaches the dosing regimens of at least two of the antibodies. Stein teaches that anti-TIM-3 antibodies can be administered for the treatment of cancer at a dose of about 400-1000 mg every two weeks, three weeks, or four weeks. [0006-0017] Stein teaches that the anti-TIM-3 agent can be used for treatment of cancer, including melanoma, endometrial cancer, and squamous cell carcinoma of the head and neck. [0032, 0064] Stein teaches that the dose of the anti-PD-1 antibody may be dosed 375-500 mg every 3 weeks or every 4 weeks. [0223-0237] Stein teaches that the antibody molecules are administered intravenously. [0020, 0074, 0439] Stein teaches that the anti-TIM-3 antibody is administered in a pharmaceutical composition comprising: sucrose and a pH 6.0. [0052-0054] Stein teaches that the antibodies may be administered sequentially or concurrently. [0077, 0178] Stein teaches that the administration or treatment produces reduction of tumor size. [0190]
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-4, 6, 34, 39-40, 46-49, 51, 57-60, 62, 68, 69, and 70-83 are rejected under 35 U.S.C. 103 as being unpatentable over Stein et al (US20200223924 A1; published 7/16/2020, in view of Lindsted et al (WO2018185232 A1; Published 10/11/2018; cited in IDS 2/20/2024), Clinical Trial NCT04370704, Record History: 4/29/2020), Shah et al (US10577422 B2; Published 5/2/2019), van Djik et al (US10639368B2; Published 12/28/2017), and Wilson et al (US10844119 B2; Published 5/10/2018)
Stein teaches a method for treating cancer in a human subject, the method comprising administering to the subject an anti-PD-1 antibody, an anti-TIM-3 antibody, and an anti-LAG-3 antibody. [0075, 0083-0085, 0124, 0128] Stein teaches the dosing regimens of at least two of the antibodies. Stein teaches that anti-TIM-3 antibodies can be administered for the treatment of cancer at a dose of about 400-1000 mg every two weeks, three weeks, or four weeks. [0006-0017] Stein teaches that the anti-TIM-3 agent can be used for treatment of cancer, including melanoma and endometrial cancer. [0032] Stein teaches that the dose of the anti-PD-1 antibody may be dosed 375-500 mg every 3 weeks or every 4 weeks. [0223-0237] Stein teaches that the antibody molecules are administered intravenously. [0020, 0074, 0439] Stein teaches that the anti-TIM-3 antibody is administered in a pharmaceutical composition comprising sucrose and has a pH 6.0. [0052-0054] Stein teaches that the antibodies may be administered sequentially or concurrently. [0077, 0178] Stein teaches that the anti-TIM-3 antibody is administered in a pharmaceutical composition comprising: sucrose and a pH 6.0. [0052-0054]
However, Stein does not teach the following:
The sequences of the anti-PD-1 antibody (claims 39, 40, 42)
The sequences of the anti-TIM-3 antibody (claims 48-49, 51 57)
The sequences of the anti-LAG-3 antibody (claims 59-60, 62, 68)
The components of the pharmaceutical composition as noted in claims 72-74
The minimum LAG-3 expression as noted in claim 79
Lindsted teaches a method for treating cancer comprising: an anti-PD-1 antibody, an anti-TIM-3 antibody, and an anti-LAG-3 antibody. Lindsted teaches that the antibody in the composition can be given once every week, every two weeks, or every three weeks. [0331] Lindsted also teaches that the antibodies can be provided in a kit. [0326] Regarding claims 47, 58 and 69, Lindsted teaches that the antibodies are administered intravenously. [0303] Regarding claim 70 and 71, Lindsted teaches that the antibodies may be administered sequentially or concurrently. Regarding claims 75-78 and 80-83, Lindsted teaches that the cancer treated is a tumor, in which a PD-1 inhibitor is indicated. [306-307] Lindsted teaches that the patient treated with the combination has been previously treated with an anti-PD-1 or anti-PD-L1 therapy, and that the tumor has acquired resistance to anti-PD-1 therapy. [0313] Lindsted teaches that the cancer treated is melanoma, squamous cell carcinoma of the head and neck, or endometrial cancer. [0036, 0307] Lindsted also exemplifies the combination of the agents in human melanoma cell lines. [Figs 11-12] Lindsted teaches that the therapy results in reduction of tumor size [0332]
Clinical trial, NCT04370704, teaches the combination of INCMGA00012 (Anti-PD-1; also known as retifanlimab), INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3) in patients with locally advanced or metastatic solid tumors in which a PD-1 inhibitor is indicated that have failed PD-1/PD-L1 therapy and patients with stage III and stage IV melanoma who relapsed during therapy with anti-PD-1 given as adjuvant therapy.
Shah teaches the use of PD-1 binding molecules, and teaches the sequences of the instantly claimed anti-PD-1 antibody. (see sequence alignments below). Shah teaches that the anti-PD-1 antibodies may be used for the treatment of cancer [col 10-11] whether it’s in combination or monotherapy [col 6] Shah teaches the combination of an anti-PD-1 antibody in combination with LAG-3 antibody. [column 14, Figure 14] Shah teaches that the antibody is administered in a pharmaceutical composition comprising: acetate, sucrose, water, and pH buffering agents. [col 125, col 121]
SEQUENCE ALIGNMENT FOR THE ANTI-PD-L1 ANTIBODY
SEQ ID NO: 1-2-3
RESULT 1
US-15-748-458-149
(NOTE: this sequence has 1 duplicate in the database searched)
Sequence 149, US/15748458
Patent No. 10577422
GENERAL INFORMATION
APPLICANT: MacroGenic, Inc.
APPLICANT: Shah, Kalpana
APPLICANT: Smith, Douglas
APPLICANT: La Motte-Mohs, Ross
APPLICANT: Johnson, Leslie
APPLICANT: Moore, Paul
APPLICANT: Bonvini, Ezio
APPLICANT: Koenig, Scott
TITLE OF INVENTION: PD-1-Binding Molecules and Methods of Use Thereof
FILE REFERENCE: 1301.0122PCT
CURRENT APPLICATION NUMBER: US/15/748,458
CURRENT FILING DATE: 2018-01-29
PRIOR APPLICATION NUMBER: US 62/198,867
PRIOR FILING DATE: 2015-07-30
PRIOR APPLICATION NUMBER: US 62/239,559
PRIOR FILING DATE: 2015-10-09
PRIOR APPLICATION NUMBER: US 62/255,140
PRIOR FILING DATE: 2015-11-13
PRIOR APPLICATION NUMBER: US 62/322,974
PRIOR FILING DATE: 2016-04-15
NUMBER OF SEQ ID NOS: 298
SEQ ID NO 149
LENGTH: 119
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: VH Domain of hPD-1 mAb 7 VH2
Query Match 86.4%; Score 156.3; Length 119;
Best Local Similarity 39.7%;
Matches 31; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 SYWMN--------------VIHPSDSETWLDQKFK------------------------- 21
||||| ||||||||||||||||
Db 31 SYWMNWVRQAPGQGLEWAGVIHPSDSETWLDQKFKDRVTITVDKSTSTAYMELSSLRSED 90
Qy 22 --------EHYGTSPFAY 31
||||||||||
Db 91 TAVYYCAREHYGTSPFAY 108
SEQ ID NO: 4-5-6
RESULT 3
US-15-748-458-291
(NOTE: this sequence has 4 duplicates in the database searched)
Sequence 291, US/15748458
Patent No. 10577422
GENERAL INFORMATION
APPLICANT: MacroGenic, Inc.
APPLICANT: Shah, Kalpana
APPLICANT: Smith, Douglas
APPLICANT: La Motte-Mohs, Ross
APPLICANT: Johnson, Leslie
APPLICANT: Moore, Paul
APPLICANT: Bonvini, Ezio
APPLICANT: Koenig, Scott
TITLE OF INVENTION: PD-1-Binding Molecules and Methods of Use Thereof
FILE REFERENCE: 1301.0122PCT
CURRENT APPLICATION NUMBER: US/15/748,458
CURRENT FILING DATE: 2018-01-29
PRIOR APPLICATION NUMBER: US 62/198,867
PRIOR FILING DATE: 2015-07-30
PRIOR APPLICATION NUMBER: US 62/239,559
PRIOR FILING DATE: 2015-10-09
PRIOR APPLICATION NUMBER: US 62/255,140
PRIOR FILING DATE: 2015-11-13
PRIOR APPLICATION NUMBER: US 62/322,974
PRIOR FILING DATE: 2016-04-15
NUMBER OF SEQ ID NOS: 298
SEQ ID NO 291
LENGTH: 271
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Second and Fourth Polypeptide Chains of DART I
Query Match 85.4%; Score 143.4; Length 271;
Best Local Similarity 41.0%;
Matches 32; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 RASESVDNYGMSFMNW--------------AASNQGS----------------------- 23
|||||||||||||||| |||||||
Db 24 RASESVDNYGMSFMNWFQQKPGQPPKLLIHAASNQGSGVPSRFSGSGSGTDFTLTISSLE 83
Qy 24 ---------QQSKEVPYT 32
|||||||||
Db 84 PEDFAVYFCQQSKEVPYT 101
SEQ ID NO: 7
RESULT 5
US-15-748-458-282
(NOTE: this sequence has 1 duplicate in the database searched)
Sequence 282, US/15748458
Patent No. 10577422
GENERAL INFORMATION
APPLICANT: MacroGenic, Inc.
APPLICANT: Shah, Kalpana
APPLICANT: Smith, Douglas
APPLICANT: La Motte-Mohs, Ross
APPLICANT: Johnson, Leslie
APPLICANT: Moore, Paul
APPLICANT: Bonvini, Ezio
APPLICANT: Koenig, Scott
TITLE OF INVENTION: PD-1-Binding Molecules and Methods of Use Thereof
FILE REFERENCE: 1301.0122PCT
CURRENT APPLICATION NUMBER: US/15/748,458
CURRENT FILING DATE: 2018-01-29
PRIOR APPLICATION NUMBER: US 62/198,867
PRIOR FILING DATE: 2015-07-30
PRIOR APPLICATION NUMBER: US 62/239,559
PRIOR FILING DATE: 2015-10-09
PRIOR APPLICATION NUMBER: US 62/255,140
PRIOR FILING DATE: 2015-11-13
PRIOR APPLICATION NUMBER: US 62/322,974
PRIOR FILING DATE: 2016-04-15
NUMBER OF SEQ ID NOS: 298
SEQ ID NO 282
LENGTH: 273
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Second Polypeptide Chain of DART H
Query Match 100.0%; Score 634; Length 273;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYWMNWVRQAPGQGLEWIGVIHPSDSETWL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYWMNWVRQAPGQGLEWIGVIHPSDSETWL 180
Qy 61 DQKFKDRVTITVDKSTSTAYMELSSLRSEDTAVYYCAREHYGTSPFAYWGQGTLVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DQKFKDRVTITVDKSTSTAYMELSSLRSEDTAVYYCAREHYGTSPFAYWGQGTLVTVSS 239
SEQ ID NO: 8
RESULT 3
US-15-748-458-291
(NOTE: this sequence has 4 duplicates in the database searched)
Sequence 291, US/15748458
Patent No. 10577422
GENERAL INFORMATION
APPLICANT: MacroGenic, Inc.
APPLICANT: Shah, Kalpana
APPLICANT: Smith, Douglas
APPLICANT: La Motte-Mohs, Ross
APPLICANT: Johnson, Leslie
APPLICANT: Moore, Paul
APPLICANT: Bonvini, Ezio
APPLICANT: Koenig, Scott
TITLE OF INVENTION: PD-1-Binding Molecules and Methods of Use Thereof
FILE REFERENCE: 1301.0122PCT
CURRENT APPLICATION NUMBER: US/15/748,458
CURRENT FILING DATE: 2018-01-29
PRIOR APPLICATION NUMBER: US 62/198,867
PRIOR FILING DATE: 2015-07-30
PRIOR APPLICATION NUMBER: US 62/239,559
PRIOR FILING DATE: 2015-10-09
PRIOR APPLICATION NUMBER: US 62/255,140
PRIOR FILING DATE: 2015-11-13
PRIOR APPLICATION NUMBER: US 62/322,974
PRIOR FILING DATE: 2016-04-15
NUMBER OF SEQ ID NOS: 298
SEQ ID NO 291
LENGTH: 271
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Second and Fourth Polypeptide Chains of DART I
Query Match 100.0%; Score 578; Length 271;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASESVDNYGMSFMNWFQQKPGQPPKLLIHAASNQGS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASESVDNYGMSFMNWFQQKPGQPPKLLIHAASNQGS 60
Qy 61 GVPSRFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPYTFGGGTKVEIK 111
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVPSRFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPYTFGGGTKVEIK 111
Van Dijk teaches a method for treating cancer comprising administering an anti-TIM3 antibody and an anti-PD-1 antibody. [col 60] Van Dijk teaches the instantly claimed sequences of the anti-TIM3 antibody. [see sequence alignments below] Van Dijk exemplifies the combination of an anti-TIM3 and an anti-PD-1 antibody in Figs 7 and 13. Van Dijk teaches that the anti-TIM-3 antibody is administered in a composition:, comprising: sodium citrate, sucrose, arginine, polysorbate 80, and pH buffering agents. [col 65-67]
SEQUENCE ALIGNMENT OF ANTI-TIM3 ANTIBODY
SEQ ID NOS: 11-12-13RESULT 1
US-15-606-148-28
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 28, US/15606148
Patent No. 10639368
GENERAL INFORMATION
APPLICANT: Agenus Inc.
TITLE OF INVENTION: ANTI-TIM-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 591907:AGBW-045
CURRENT APPLICATION NUMBER: US/15/606,148
CURRENT FILING DATE: 2017-05-26
PRIOR APPLICATION NUMBER: US 62/342,610
PRIOR FILING DATE: 2016-05-27
PRIOR APPLICATION NUMBER: US 62/420,276
PRIOR FILING DATE: 2016-11-10
NUMBER OF SEQ ID NOS: 102
SEQ ID NO 28
LENGTH: 120
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: AM-2-VH
Query Match 85.8%; Score 150.2; Length 120;
Best Local Similarity 39.2%;
Matches 31; Conservative 0; Mismatches 0; Indels 48; Gaps 2;
Qy 1 RQNAWSW-----------VSAISGSGGSTY------------------------------ 19
||||||| ||||||||||||
Db 30 RQNAWSWVRRAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAE 89
Qy 20 -------AKGGDYGGNYFD 31
||||||||||||
Db 90 DTAVYYCAKGGDYGGNYFD 108
SEQ ID NOS: 14-15-16
RESULT 1
US-15-606-148-45
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 45, US/15606148
Patent No. 10639368
GENERAL INFORMATION
APPLICANT: Agenus Inc.
TITLE OF INVENTION: ANTI-TIM-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 591907:AGBW-045
CURRENT APPLICATION NUMBER: US/15/606,148
CURRENT FILING DATE: 2017-05-26
PRIOR APPLICATION NUMBER: US 62/342,610
PRIOR FILING DATE: 2016-05-27
PRIOR APPLICATION NUMBER: US 62/420,276
PRIOR FILING DATE: 2016-11-10
NUMBER OF SEQ ID NOS: 102
SEQ ID NO 45
LENGTH: 107
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: BADD466-3170 VL
Query Match 81.0%; Score 105.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RASQSVSSYLA---------------DASNRAT--------------------------- 18
||||||||||| |||||||
Db 24 RASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDF 83
Qy 19 -----QQYGSSPLT 27
|||||||||
Db 84 AVYYCQQYGSSPLT 97
SEQ ID NOS: 17
RESULT 1
US-15-606-148-28
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 28, US/15606148
Patent No. 10639368
GENERAL INFORMATION
APPLICANT: Agenus Inc.
TITLE OF INVENTION: ANTI-TIM-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 591907:AGBW-045
CURRENT APPLICATION NUMBER: US/15/606,148
CURRENT FILING DATE: 2017-05-26
PRIOR APPLICATION NUMBER: US 62/342,610
PRIOR FILING DATE: 2016-05-27
PRIOR APPLICATION NUMBER: US 62/420,276
PRIOR FILING DATE: 2016-11-10
NUMBER OF SEQ ID NOS: 102
SEQ ID NO 28
LENGTH: 120
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: AM-2-VH
Query Match 100.0%; Score 640; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFRQNAWSWVRRAPGKGLEWVSAISGSGGSTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFRQNAWSWVRRAPGKGLEWVSAISGSGGSTYY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGDYGGNYFDYWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGDYGGNYFDYWGQGTLVTVSS 120
SEQ ID NOS: 18
RESULT 1
US-15-606-148-46
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 46, US/15606148
Patent No. 10639368
GENERAL INFORMATION
APPLICANT: Agenus Inc.
TITLE OF INVENTION: ANTI-TIM-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 591907:AGBW-045
CURRENT APPLICATION NUMBER: US/15/606,148
CURRENT FILING DATE: 2017-05-26
PRIOR APPLICATION NUMBER: US 62/342,610
PRIOR FILING DATE: 2016-05-27
PRIOR APPLICATION NUMBER: US 62/420,276
PRIOR FILING DATE: 2016-11-10
NUMBER OF SEQ ID NOS: 102
SEQ ID NO 46
LENGTH: 107
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: BADD466-3171 VL
Query Match 100.0%; Score 549; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
Qy 61 SFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIK 107
SEQ ID NO: 19
RESULT 1
US-15-606-148-61
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 61, US/15606148
Patent No. 10639368
GENERAL INFORMATION
APPLICANT: Agenus Inc.
TITLE OF INVENTION: ANTI-TIM-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 591907:AGBW-045
CURRENT APPLICATION NUMBER: US/15/606,148
CURRENT FILING DATE: 2017-05-26
PRIOR APPLICATION NUMBER: US 62/342,610
PRIOR FILING DATE: 2016-05-27
PRIOR APPLICATION NUMBER: US 62/420,276
PRIOR FILING DATE: 2016-11-10
NUMBER OF SEQ ID NOS: 102
SEQ ID NO 61
LENGTH: 449
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: AM-2 full length IgG1 N297A heavy chain
Query Match 100.0%; Score 2400; Length 449;
Best Local Similarity 100.0%;
Matches 449; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFRQNAWSWVRRAPGKGLEWVSAISGSGGSTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFRQNAWSWVRRAPGKGLEWVSAISGSGGSTYY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGDYGGNYFDYWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGDYGGNYFDYWGQGTLVTVSS 120
Qy 121 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 180
Qy 181 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG 240
Qy 241 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA 300
Qy 301 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 360
Qy 361 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 420
Qy 421 QQGNVFSCSVMHEALHNHYTQKSLSLSPG 449
|||||||||||||||||||||||||||||
Db 421 QQGNVFSCSVMHEALHNHYTQKSLSLSPG 449
SEQ ID NO: 20
RESULT 1
US-15-606-148-69
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 69, US/15606148
Patent No. 10639368
GENERAL INFORMATION
APPLICANT: Agenus Inc.
TITLE OF INVENTION: ANTI-TIM-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 591907:AGBW-045
CURRENT APPLICATION NUMBER: US/15/606,148
CURRENT FILING DATE: 2017-05-26
PRIOR APPLICATION NUMBER: US 62/342,610
PRIOR FILING DATE: 2016-05-27
PRIOR APPLICATION NUMBER: US 62/420,276
PRIOR FILING DATE: 2016-11-10
NUMBER OF SEQ ID NOS: 102
SEQ ID NO 69
LENGTH: 214
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: BADD466-3171 full length light chain sequence
Query Match 100.0%; Score 1102; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
Qy 61 SFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Wilson teaches a method of treating cancer comprising administering an anti-LAG-3 antibody. Wilson teaches the instantly claimed sequences of the anti-LAG-3 antibody (see sequence alignment below). Wilson teaches and exemplifies the combination of an anti-LAG-3 antibody with an anti-PD-1 antibody. [see figure 9; col 7 7, lines 10-25) Wilson also teaches that the antibody may be further administered with an anti-TIM3 antibody. [col 84, lines 3-16] Wilson teaches that the cancer treated may be melanoma, and that the antibody is administered intravenously. [col 18, col 82] Wilson teaches assaying for the expression of LAG-3 and comparing to the standard of a person not having the disorder. Wilson teaches that the standard LAG-3 polypeptide level is known and can be used repeatedly as a standard of comparison. [col 91, lines 30-52] Wilson teaches that the anti-LAG-3 antibody is administered in a pharmaceutical composition comprising: sodium acetate, trehalose, and polysorbate 80. [col 78-79]
SEQUENCE ALIGNMENT OF ANTI-LAG-3 ANTIBODY
SEQ ID NOS: 21-22-23
RESULT 1
US-15-730-249-72
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 72, US/15730249
Patent No. 10844119
GENERAL INFORMATION
APPLICANT: AGENUS INC.
TITLE OF INVENTION: ANTI-LAG-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 595073:AGBW-046
CURRENT APPLICATION NUMBER: US/15/730,249
CURRENT FILING DATE: 2017-10-11
PRIOR APPLICATION NUMBER: 62/420,280
PRIOR FILING DATE: 2016-11-10
PRIOR APPLICATION NUMBER: 62/406,766
PRIOR FILING DATE: 2016-10-11
NUMBER OF SEQ ID NOS: 228
SEQ ID NO 72
LENGTH: 121
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 87.7%; Score 175.4; Length 121;
Best Local Similarity 42.5%;
Matches 34; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 DTYIH--------------EIDPANDNTKYDPKFQG------------------------ 22
||||| |||||||||||||||||
Db 31 DTYIHWVRQAPGQGLEWMGEIDPANDNTKYDPKFQGRVTITADTSSNTVYMELSSLRSED 90
Qy 23 --------YYYKYDVGGFDY 34
||||||||||||
Db 91 TAVYYCATYYYKYDVGGFDY 110
SEQ ID NOS: 24-25-26
RESULT 1
US-15-730-249-10
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 10, US/15730249
Patent No. 10844119
GENERAL INFORMATION
APPLICANT: AGENUS INC.
TITLE OF INVENTION: ANTI-LAG-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 595073:AGBW-046
CURRENT APPLICATION NUMBER: US/15/730,249
CURRENT FILING DATE: 2017-10-11
PRIOR APPLICATION NUMBER: 62/420,280
PRIOR FILING DATE: 2016-11-10
PRIOR APPLICATION NUMBER: 62/406,766
PRIOR FILING DATE: 2016-10-11
NUMBER OF SEQ ID NOS: 228
SEQ ID NO 10
LENGTH: 108
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 82.5%; Score 116.3; Length 108;
Best Local Similarity 37.3%;
Matches 28; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 SVSSSISSSNLH---------------GTSNLAS-------------------------- 19
|||||||||||| |||||||
Db 24 SVSSSISSSNLHWFQQKSGTSPKLWIYGTSNLASGVPVRFSGSGSGTSYSLTISSMEAED 83
Qy 20 ------QQWSSYPFT 28
|||||||||
Db 84 AATYYCQQWSSYPFT 98
SEQ ID NO: 27
RESULT 1
US-15-730-249-65
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 65, US/15730249
Patent No. 10844119
GENERAL INFORMATION
APPLICANT: AGENUS INC.
TITLE OF INVENTION: ANTI-LAG-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 595073:AGBW-046
CURRENT APPLICATION NUMBER: US/15/730,249
CURRENT FILING DATE: 2017-10-11
PRIOR APPLICATION NUMBER: 62/420,280
PRIOR FILING DATE: 2016-11-10
PRIOR APPLICATION NUMBER: 62/406,766
PRIOR FILING DATE: 2016-10-11
NUMBER OF SEQ ID NOS: 228
SEQ ID NO 65
LENGTH: 121
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 100.0%; Score 648; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQMVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQGLEWMGEIDPANDNTKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQMVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQGLEWMGEIDPANDNTKY 60
Qy 61 DPKFQGRVTITADTSTSTVYMELSSLRSEDTAVYYCATYYYKYDVGGFDYWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DPKFQGRVTITADTSTSTVYMELSSLRSEDTAVYYCATYYYKYDVGGFDYWGQGTLVTVS 120
Qy 121 S 121
|
Db 121 S 121
SEQ ID NO: 28
RESULT 1
US-15-730-249-73
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 73, US/15730249
Patent No. 10844119
GENERAL INFORMATION
APPLICANT: AGENUS INC.
TITLE OF INVENTION: ANTI-LAG-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 595073:AGBW-046
CURRENT APPLICATION NUMBER: US/15/730,249
CURRENT FILING DATE: 2017-10-11
PRIOR APPLICATION NUMBER: 62/420,280
PRIOR FILING DATE: 2016-11-10
PRIOR APPLICATION NUMBER: 62/406,766
PRIOR FILING DATE: 2016-10-11
NUMBER OF SEQ ID NOS: 228
SEQ ID NO 73
LENGTH: 108
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 100.0%; Score 564; Length 108;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPGTLSLSPGERATLSCSVSSSISSSNLHWYQQKPGQAPRLLIYGTSNLASGIP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPGTLSLSPGERATLSCSVSSSISSSNLHWYQQKPGQAPRLLIYGTSNLASGIP 60
Qy 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWSSYPFTFGQGTKVEIK 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWSSYPFTFGQGTKVEIK 108
SEQ ID NO: 29
RESULT 1
US-15-730-249-169
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 169, US/15730249
Patent No. 10844119
GENERAL INFORMATION
APPLICANT: AGENUS INC.
TITLE OF INVENTION: ANTI-LAG-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 595073:AGBW-046
CURRENT APPLICATION NUMBER: US/15/730,249
CURRENT FILING DATE: 2017-10-11
PRIOR APPLICATION NUMBER: 62/420,280
PRIOR FILING DATE: 2016-11-10
PRIOR APPLICATION NUMBER: 62/406,766
PRIOR FILING DATE: 2016-10-11
NUMBER OF SEQ ID NOS: 228
SEQ ID NO 169
LENGTH: 450
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 100.0%; Score 2408; Length 450;
Best Local Similarity 100.0%;
Matches 450; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQMVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQGLEWMGEIDPANDNTKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQMVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQGLEWMGEIDPANDNTKY 60
Qy 61 DPKFQGRVTITADTSTSTVYMELSSLRSEDTAVYYCATYYYKYDVGGFDYWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DPKFQGRVTITADTSTSTVYMELSSLRSEDTAVYYCATYYYKYDVGGFDYWGQGTLVTVS 120
Qy 121 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
Qy 181 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLG 240
Qy 241 GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 300
Qy 301 ASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 ASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE 360
Qy 361 EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 420
Qy 421 WQQGNVFSCSVMHEALHNHYTQKSLSLSPG 450
||||||||||||||||||||||||||||||
Db 421 WQQGNVFSCSVMHEALHNHYTQKSLSLSPG 450
SEQ ID NO: 30
RESULT 1
US-15-730-249-187
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 187, US/15730249
Patent No. 10844119
GENERAL INFORMATION
APPLICANT: AGENUS INC.
TITLE OF INVENTION: ANTI-LAG-3 ANTIBODIES AND METHODS OF USE THEREOF
FILE REFERENCE: 595073:AGBW-046
CURRENT APPLICATION NUMBER: US/15/730,249
CURRENT FILING DATE: 2017-10-11
PRIOR APPLICATION NUMBER: 62/420,280
PRIOR FILING DATE: 2016-11-10
PRIOR APPLICATION NUMBER: 62/406,766
PRIOR FILING DATE: 2016-10-11
NUMBER OF SEQ ID NOS: 228
SEQ ID NO 187
LENGTH: 215
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 100.0%; Score 1117; Length 215;
Best Local Similarity 100.0%;
Matches 215; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPGTLSLSPGERATLSCSVSSSISSSNLHWYQQKPGQAPRLLIYGTSNLASGIP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPGTLSLSPGERATLSCSVSSSISSSNLHWYQQKPGQAPRLLIYGTSNLASGIP 60
Qy 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWSSYPFTFGQGTKVEIKRTVAAPSVFIFP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWSSYPFTFGQGTKVEIKRTVAAPSVFIFP 120
Qy 121 PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL 180
Qy 181 TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 215
|||||||||||||||||||||||||||||||||||
Db 181 TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 215
It is noted that claims 39, 40, and 42, 48-49, 51 and 57, and 59-60, 62, and 68 require that the anti-PD-1 agent, the anti-TIM-3 agent, and the anti-LAG-3 agents comprise respective antibodies with instantly claimed sequences. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the instantly claimed antibodies with the antibodies of Stein for the treatment of cancer. One would have been motivated to, and have a reasonable expectation of success, because: (1) Stein, Lindsted and the clinical trial all teach known methods for treating cancer, comprising administering to a patient an anti-PD-1 antibody, an anti-TIM-3 antibody, and an anti-LAG-3 antibody, (2) Shah teaches and exemplifies the use of the instantly claimed anti-PD-1 antibody for the treatment of cancer, and teaches the combination with an anti-LAG-3 antibody, (3) van Dijk teaches and exemplifies a method for treating cancer comprising administering an anti-TIM3 antibody and an anti-PD-1 antibody, and teaches the instantly claimed sequences of the anti-TIM3 antibody, and (4) Wilson teaches a method for treating cancer comprising administering the instantly claimed anti-LAG-3 antibody, and teaches and exemplifies this antibody in combination with an anti-PD- antibody. One of skill in the art could have substituted one antibody for another, and the results of treatment of cancer, would have been predictable.
MPEP 2144.06 Art Recognized Equivalence for the Same Purpose [R-08.2012]
II. SUBSTITUTING EQUIVALENTS KNOWN FOR THE SAME PURPOSE
In order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art, and cannot be based on applicant’s disclosure or the mere fact that the components at issue are functional or mechanical equivalents. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958) (The mere fact that components are claimed as members of a Markush group cannot be relied upon to establish the equivalency of these components. However, an applicant’s expressed recognition of an art-recognized or obvious equivalent may be used to refute an argument that such equivalency does not exist.); Smith v. Hayashi, 209 USPQ 754 (Bd. of Pat. Inter. 1980) (The mere fact that phthalocyanine and selenium function as equivalent photoconductors in the claimed environment was not sufficient to establish that one would have been obvious over the other. However, there was evidence that both phthalocyanine and selenium were known photoconductors in the art of electrophotography. "This, in our view, presents strong evidence of obviousness in substituting one for the other in an electrophotographic environment as a photoconductor." 209 USPQ at 759.).
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An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).
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It is noted that claim 79 requires that the tumor has a minimum LAG-3 expression greater than or equal to 5% of LAG-3 positive immune cells within the tumor region. This limitation would have been obvious to those of ordinary skill in the art because: (1) Stein, Lindsted and the clinical trial all teach known methods for treating cancer, comprising administering to a patient an anti-PD-1 antibody, an anti-TIM-3 antibody, and an anti-LAG-3 antibody, (2) Wilson teaches a method for treating cancer comprising administering the instantly claimed anti-LAG-3 antibody, and teaches and exemplifies this antibody in combination with an anti-PD- antibody, and (4) Wilson teaches assaying for the expression of LAG-3 and comparing to the standard of a person not having the disorder. Wilson teaches that the standard LAG-3 polypeptide level is known and can be used repeatedly as a standard of comparison. Given the need to treat tumors with increased LAG-3 expression, and given the known methods of treating tumors with anti-LAG-3 antibodies, one of skilled in the art could have pursued treating tumors with increased LAG-3 expression, with a reasonable expectation of success.
It is noted that claims 72-74 requires that the claimed agents are administered in specific pharmaceutical compositions. This limitation would have been obvious to those of ordinary skill in the art because: (1) Stein teaches the pharmaceutical composition of an anti-PD-1 antibody and teaches that this antibody comprises sucrose and has a pH of 6.0, (2) Shah teaches that the anti-PD-1 antibody is administered in a pharmaceutical composition comprising: acetate, sucrose, water, and pH buffering agents, (3) Van Dijk teaches that the anti-TIM-3 antibody is administered in a composition:, comprising: sodium citrate, sucrose, arginine, polysorbate 80, and pH buffering agents, and (4) Wilson teaches that the anti-LAG-3 antibody is administered in a pharmaceutical composition comprising: sodium acetate, trehalose, and polysorbate 80. Given the known methods of formulating pharmaceutical compositions, and given the known components of each agent as claimed, one of skilled in the art could have administered the specific agents in the specific pharmaceutical composition comprising the agents, with a reasonable expectation of success.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-4, 6, 34, 39-40, 42, 46-49, 51, 57-60, 62, and 68-83 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-10 and 34-85 of copending Application No. 18/600,262 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Conclusion
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600