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 .
Applicant’s elections and remarks filed 5-26-26 are acknowledged.
Applicant elects the invention of Group I, without traverse, and further responds to the following election of species requirements:
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As follows:
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Upon reconsideration the prior restriction requirement between the inventions of Groups I and II has been withdrawn.
Claims 1, 3, 4, 6, 10, 12, 14, 16, 18-25, 27, 28 and 31-33 are pending.
Claims 1, 3, 4, 6, 10, 12, 14, 16, 18-25, 27, 28 and 31 are under consideration as they read on the species of invention
wherein the fluoropyrimidine compound is “5-FU;”
wherein the platinum-based therapy is oxaliplatin;
wherein the antibody has the VH and VL of SEQ ID NOs: 32 and 39;
wherein the anti-PD-1 antibody is pembrolizumab;
wherein the anti-PD-L1 antibody is durvalumab; and
wherein the cancer is adenocarcinoma.
Claims 32 and 33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5-26-26.
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.
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, 3, 4, 6, 10, 12, 14, 16, 18-25, 27, 28 and 31 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Yamada et al. (WO2021024020, cited on an IDS), or, in the alternative, as obvious over the teachings of Yamada et al. (WO2021024020).
Yamada teaches the treatment of gastric and esophageal cancers by administering an anti-CLDN18.2 antibody in combination with fluourouracil- and platinum-based chemotherapeutic agents (see pages 1-2, 1st and 2nd paragraphs of each).
At page 2, 2nd full paragraph Yamada teaches a clinically tested, anti-CLDN18.2 antibody known as IMAB362 / Zolbetuximab / Claudiximab which comprises heavy and light chains of SEQ ID NOs: 51 and 24, said antibody “recogniz[ing] the first extracellular domain (ECD1) of CLDN18.2 with high affinity and specificity,” wherein “IMAB362 shows precise tumor cell specificity and bundles two independent highly potent mechanisms of action. Upon target binding IMAB362 mediates cell killing mainly by ADCC and CDC.”
Heavy chain SEQ ID NOs: 17, 32 and 51 of the instant claims are identical to heavy chain SEQ ID NOs: 17, 32 and 51 of Yamada, while light chain SEQ ID NOs: 24 and 39 of the instant claims are identical to light chain SEQ ID NOs: 24 and 39 of Yamada.
As shown in the Table at page 71, clone “175D10” corresponding to mAb “182-D1106-362” is an IgG1 antibody comprising the heavy chain sequences of SEQ ID NOs: 32 and 17 and the light chain sequences of SEQ ID NOs: 39 and 24. Moreover, at page 70, final paragraph Yamada teaches that anti-CLDN18.2 antibodies can be obtained from various hydridoma cell lines deposited at the DSMZ, including e.g., accession number DSM ACC2810 (corresponding to clone “182-D1106-362.”
At page 7, 5th full paragraph – page 9, 1st full paragraph, Yamada teaches composition, kits comprising said compositions, and there use in methods of treating cancer:
“In one embodiment of all aspects disclosed herein, the medical preparation further includes printed instructions for use of the preparation for treatment of cancer.
In one embodiment of all aspects disclosed herein, the medical preparation is a composition comprising the anti-CLDN18.2 antibody and the immune checkpoint inhibitor.
In one embodiment of all aspects disclosed herein, the method of the invention further comprises administering a cytotoxic and/or cytostatic agent. In one embodiment of all aspects disclosed herein, the medical preparation of the invention further comprises a cytotoxic and/or cytostatic agent.
The cytotoxic and/or cytostatic agent may be an agent stabilizing or increasing expression of CLDN18.2. Expression of CLDN18.2 is preferably at the cell surface of a cancer cell. In one embodiment, the cytotoxic and/or cytostatic agent comprises an agent which induces a cell cycle arrest or an accumulation of cells in one or more phases of the cell cycle, preferably in one or more phases of the cell cycle other than the G1 -phase. The cytotoxic and/or cytostatic agent may comprise an agent selected from the group consisting of anthracyclines, platinum compounds, nucleoside analogs, taxanes, and camptothecin analogs, or prodrugs thereof, and combinations thereof. The cytotoxic and/or cytostatic agent may comprise an agent selected from the group consisting of epirubicin, oxaliplatin, cisplatin, 5-fluorouracil or prodrugs thereof such as capecitabine, docetaxel, irinotecan, and combinations thereof. The cytotoxic and/or cytostatic agent may comprise a combination of oxaliplatin and 5-fluorouracil or prodrugs thereof, a combination of cisplatin and 5-fluorouracil or prodrugs thereof, a combination of at least one anthracycline and oxaliplatin, a combination of at least one anthracycline and cisplatin, a combination of at least one anthracycline and 5-fluorouracil or prodrugs thereof, a combination of at least one taxane and oxaliplatin, a combination of at least one taxane and cisplatin, a combination of at least one taxane and 5-fluorouracil or prodrugs thereof, or a combination of at least one camptothecin analog and 5-fluorouracil or prodrugs thereof. The cytotoxic and/or cytostatic agent may be an agent inducing immunogenic cell death. The agent inducing immunogenic cell death may comprise an agent selected from the group consisting of anthracyclines, oxaliplatin and combinations thereof. The cytotoxic and/or cytostatic agent may comprise a combination of epirubicin and oxaliplatin. In one embodiment, the method of the invention comprises administering at least one anthracycline, at least one platinum compound and at least one of 5-fluorouracil and prodrugs thereof. In one embodiment, the medical preparation of the invention comprises at least one anthracycline, at least one platinum compound and at least one of 5-fluorouracil and prodrugs thereof. The anthracycline may be selected from the group consisting of epirubicin, doxorubicin, daunorubicin, idarubicin and valrubicin. Preferably, the anthracycline is epirubicin. The platinum compound may selected from the group consisting of oxaliplatin and cisplatin. The nucleoside analog may be selected from the group consisting of 5-fluorouracil and prodrugs thereof. The taxane may be selected from the group consisting of docetaxel and paclitaxel. The camptothecin analog may be selected from the group consisting of irinotecan and topotecan. In one embodiment, the method of the invention comprises administering (i) epirubicin, oxaliplatin and 5-fluorouracil, (ii) epirubicin, oxaliplatin and capecitabine, (iii) epirubicin, cisplatin and 5-fluorouracil, (iv) epirubicin, cisplatin and capecitabine, (v) folinic acid, oxaliplatin and 5-fluorouracil, (vi) folinic acid, oxaliplatin and capecitabine, or (vii) oxaliplatin and capecitabine. In one embodiment, the medical preparation of the invention comprises (i) epirubicin, oxaliplatin and 5-fluorouracil, (ii) epirubicin, oxaliplatin and capecitabine, (iii) epirubicin, cisplatin and 5-fluorouracil, (iv) epirubicin, cisplatin and capecitabine, (v) folinic acid, oxaliplatin and 5-fluorouracil, (vi) folinic acid, oxaliplatin and capecitabine, or (vii) oxaliplatin and capecitabine.
The anti-CLDN18.2 antibody and the immune checkpoint inhibitor, and optionally the cytotoxic and/or cytostatic agent, may be present in the medical preparation in a mixture or separate from each other. The medical preparation may be a kit comprising a first container including the CLDN18.2 antibody and a container including the immune checkpoint inhibitor, and optionally a container including the cytotoxic and/or cytostatic agent. The medical preparation may further include printed instructions for use of the preparation for treatment of cancer, in particular for use of the preparation in a method of the invention. Different embodiments of the medical preparation, and, in particular, of the immune checkpoint inhibitor and the cytotoxic and/or cytostatic agent are as described above for the method of the invention.
The present invention also provides the agents described herein such as the anti-CLDN18.2 antibody and the immune checkpoint inhibitor for use in therapy. In one embodiment, such therapy comprises treating and/or preventing diseases associated with cells expressing CLDN18.2, including cancer diseases such as those described herein.
The present invention also provides the agents described herein such as the anti-CLDN18.2 antibody for use in the methods described herein, e.g. for administration in combination with an immune checkpoint inhibitor, and optionally a cytotoxic and/or cytostatic agent. The present invention also provides a use of the agents described herein such as the anti-CLDN18.2 antibody for the preparation of a pharmaceutical composition for use in the methods described herein, e.g. for administration in combination with an immune checkpoint inhibitor, and optionally a cytotoxic and/or cytostatic agent.”
With respect to the particular checkpoint inhibitors to be used, Yamada teaches the anti-PD-1 inhibitor can be the pembrolizumab antibody (see, e.g., at page 4-5 bridging paragraph) while the anti-PD-L1 inhibitor can be the durvalumab antibody (see page 5, 1st full paragraph).
With respect to the particular cytotoxic and/or cytostatic agents, Yamada teaches a variety of such agents both induce cell cycle arrest and are further capable of “stabilizing or increasing expression of CLDN18.2," see at page 50-51 bridging paragraph, wherein cytotoxic and/or cytostatic agents having said properties include combinations of 5-fluorouracil and oxaliplatin, see e.g., at page 51, 1st full paragraph: “According to the invention, the term "agent stabilizing or increasing expression of CLDN18.2" includes anthracyclines such as epirubicin, platinum compounds such as oxaliplatin and cisplatin, nucleoside analogs such as 5-fluorouracil or prodrugs thereof, taxanes such as docetaxel, and camptothecin analogs such as irinotecan and topotecan, and combinations of drugs such as combinations of drugs comprising one or more of anthracyclines such as epirubicin, oxaliplatin and 5-fluorouracil such as a combination of drugs comprising oxaliplatin and 5-fluorouracil or other drug combinations described herein.”
Finally, claims 1-24 of Yamada are drawn to method for treating or preventing cancer in a patient, comprising administering to the patient an anti-CLDN 18.2 antibody and an immune checkpoint inhibitor wherein the anti-CLDN18.2 antibody is administered “at a dose of up to 1000 mg/m2” (see claim 19), “wherein the cancer is CLDN18.2 positive” (see claim 21) , e.g., various types of “cancer of the esophagus.” (see claim 23).
Thus, the teachings of Yamada anticipate claims 1, 3, 4, 6, 10, 12, 14, 16, 18-25, 27, 28 and 31.
Moreover, insofar as applicant were to attempt to argue that the teaching of Yamada are non-anticipatory (to which the undersigned would disagree), the claimed invention is at least obvious in view of the teachings of Yamada.
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, 3, 4, 6, 10, 12, 14, 16, 18-25, 27, 28 and 31 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 a method for treating a CLDN18.2-expressing cancer in a patient, or for inhibiting growth of a CLDN18.2-expressing tumor in a patient having cancer, comprising administering to the patient an anti-CLDN18.2 antibody, a platinum compound, a fluoropyrimidine compound or precursor thereof and an immune checkpoint inhibitor selected from a PD-1 inhibitor and a PD-L1 inhibitor, does not reasonably provide enablement for the breadth of the instant claims which encompass treating any cancer, or preventing any cancer in a patient or for inhibiting growth of any tumor in a patient having cancer by administering to the patient an anti-CLDN18.2 antibody, a platinum compound, a fluoropyrimidine compound or precursor thereof and an immune checkpoint inhibitor selected from a PD-1 inhibitor and a PD-L1 inhibitor, and further for the breadth of claims as they encompass a method for treating cancer in a patient, or for inhibiting growth of a tumor in a patient having cancer, comprising administering to the patient an anti-CLDN18.2 antibody, a platinum compound, a fluoropyrimidine compound or precursor thereof and an immune checkpoint inhibitor selected from a PD-1 inhibitor and a PD-L1 inhibitor, wherein said anti-CLDN18.2 antibody is as set forth in claim 18(iii).
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.
First, with respect to treating any cancer or for inhibiting growth of any tumor in a patient having cancer by administering to the patient an anti-CLDN18.2 antibody, a platinum compound, a fluoropyrimidine compound or precursor thereof and an immune checkpoint inhibitor selected from a PD-1 inhibitor and a PD-L1 inhibitor, as described by Dottermusch in the section entitled “CLDN18.2 expression is decreased in gastric cancer” (see page 570, col. bridging section), “The majority of GCs of our cohort was completely devoid of any CLDN18.2 expression, while a large proportion of positive GCs showed solely weak staining levels,” thus emphasizing the importance of ensuring a given patient’s cancer expresses CLDN18.2 at sufficient levels to allow the anti-CLDN18.2 antibody to bind to and mediate ADCC- and/or CDC-dependent lysis (see Dottermusch et al., Virchows Archiv (2019) 475:563–571, and supplemental pages 1-4, cited herewith). Along these same lines, as described in the first full paragraph on page 570 of Dottermusch, their extent of CLDN18.2 expression is inversely correlated with the invasiveness of the tumor cells, thus further emphasizing the importance of ensuring a given patient’s cancer expresses CLDN18.2 at sufficient levels to allow the anti-CLDN18.2 antibody to bind to and mediate ADCC- and/or CDC-dependent lysis.
Thus, the ordinarily skilled artisan would not know how to treat, in the absence of undue experimentation the vast breadth of cancers which do not express CLDN18.2 by administering to the patient an anti-CLDN18.2 antibody, a platinum compound, a fluoropyrimidine compound or precursor thereof and an immune checkpoint inhibitor selected from a PD-1 inhibitor and a PD-L1 inhibitor.
Second, according to the specification at page 20, 2nd full paragraph, “The terms ‘prophylactic treatment’ or ‘preventive treatment’ relate to any treatment that is intended to prevent a disease from occurring in an individual. The terms ‘prophylactic treatment’ or ‘preventive treatment’ are used herein interchangeably.”
Thus, the instant claims given their broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art encompass in their breadth methods for preventing cancer from occurring in a patient, i.e., a method whereby a patient can be prospectively treated prior to detection of cancer, and thereby avoid getting cancer. However, as has been long known in the art, the etiology of cancer is complicated and poorly understood, and as a consequence the skilled artisan is generally unable to say in advance, with any reasonable degree of certainty and precision, who will eventually develop any one or more of hundreds of different types of cancer falling into these vast genera. For example, it was known in the art that many potential factors were hypothesized to cause a person to be at risk of a brain tumor, only for subsequent work to show these putative factors to have no predictive value (see, e.g., McKinney, J Neurol Neurosurg Psychiatry 2004;75(Suppl II):ii12–ii17, at pages ii15-16, cited herewith). Thus, the skilled artisan would certainly not prospectively treat a patient for a potential brain cancer based on the presence of such uncertain factors.
Similarly, the ordinarily skilled artisan could not “prevent cancer” as recited in the instant claims when the instant specification provides insufficient direction or guidance to predict which patients will eventually develop a cancer that can be treated as claimed.
Third, with respect to claim 18, part (iii) (“[t]he method of claim 1, wherein the anti-CLDN18.2 antibody is an antibody selected from the group consisting of: (i) an antibody produced by and/or obtainable from a clone deposited under the accession no. DSM ACC2737, DSM ACC2738, DSM ACC2739, DSM ACC2740, DSM ACC2741, DSM ACC2742, DSM ACC2743, DSM ACC2745, DSM ACC2746, DSM ACC2747, DSM ACC2748, DSM ACC2808, DSM ACC2809, or DSM ACC2810…(iii) an antibody having the specificity of the antibody under (i)….”), at page 69-70 bridging paragraph the specification discloses (emphasis added):
“Two binding molecules have the “same specificity” if they bind to the same antigen and to the same epitope. Whether a molecule to be tested recognizes the same epitope as a certain binding molecule, i.e., the binding molecules bind to the same epitope, can be tested by different methods known to the skilled person. The competition of the binding molecules such as antibodies for the same epitope may provide an indication for the binding molecules binding to the same epitope. The competition between the binding molecules can be detected by a cross-blocking assay. For example, a competitive ELISA assay may be used as a cross-blocking assay. For example, target antigen may be coated on the wells of a microtiter plate and antigen binding antibody and candidate competing test antibody may be added. The amount of the antigen binding antibody bound to the antigen in the well indirectly correlates with the binding ability of the candidate competing test antibody that competes therewith for binding to the same epitope. Specifically, the larger the affinity of the candidate competing test antibody is for the same epitope, the smaller the amount of the antigen binding antibody bound to the antigen-coated well. The amount of the antigen binding antibody bound to the well can be measured by labeling the antibody with detectable or measurable labeling substances.”
Further to the above, at page 27, 1st and 2nd full paragraphs (emphasis added), the specification further instructs:
“In a preferred embodiment, an antibody that is an immune checkpoint inhibitor, is an isolated antibody. The antibody that is an immune checkpoint inhibitor or the antigen-binding fragment thereof according to the present disclosure may also be an antibody that cross-competes for antigen binding with any known immune checkpoint inhibitor antibody. In certain embodiments, an immune checkpoint inhibitor antibody cross-competes with one or more of the immune checkpoint inhibitor antibodies described herein. The ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies may bind to the same epitope region of the antigen or when binding to another epitope sterically hinder the binding of known immune checkpoint inhibitor antibodies to that particular epitope region. These cross- competing antibodies may have functional properties very similar to those they are cross- competing with as they are expected to block binding of the immune checkpoint to its ligand either by binding to the same epitope or by sterically hindering the binding of the ligand. Cross-competing antibodies can be readily identified based on their ability to cross-compete with one or more of known antibodies in standard binding assays such as Surface Plasmon Resonance analysis, ELISA assays or flow cytometry (see, e.g., WO 2013/173223).
In certain embodiments, antibodies or antigen binding fragments thereof that cross-compete for binding to a given antigen with or bind to the same epitope region of a given antigen as, one or more known antibodies are monoclonal antibodies. For administration to human patients, these cross-competing antibodies can be chimeric antibodies, or humanized or human antibodies. Such chimeric, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.”
In view of the above, part (iii) of claim 18, given its broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art, would be understood to refer to the genus of antibodies that “bind to the same antigen and to the same epitope,” which would necessarily not include, e.g., those antibodies that “cross compete” with the antibodies of claim 18(i) by binding to another epitope and sterically hindering the binding of the antibodies of claim 18(i) to their particular “epitope.”
Rather, the ordinarily skilled artisan would understand claim 18(iii) to be drawn to only those antibodies that bind CLDN18.2 via the same bonding pattern as the antibodies recited in claim 18(i), i.e., by making use of the same antibody atoms to contact the same CLDN18.2 atoms via the same molecular interactions (the same hydrogen bonds, the same covalent bonds, the same ionic bonds, etc.) by which the antibodies recited in claim 18(i) bind to CLDN18.2.
However, in order to show any given antibody has “the specificity of the antibody of claim 18(i)” as recited in 18(iii), the ordinarily skilled artisan would have to perform undue experimentation to determine the precise epitope(s) of CLDN18.2 to which the antibodies of claim 18(iii) bind.
For example, as taught by Wu et al. 20080171014 (cited herewith), the mapping of epitopes to which various anti-IL-13 antibodies bind required forming antibody-ag complexes and performing proteolysis followed by mass spectroscopy to detect the regions of IL-13 protected through antibody binding (see example 2.2.3.b on page 51-52). Wu further described how the preparation of an anti-IL-13 : IL-13 crystal and subsequent crystal structure analysis were required to determine the antibody actual bound epitope (see examples 2.3-2.3.6 on pages 52-53). Notably, the proteolytic assay failed to identify one of the two IL-13 regions bound by the anti-IL-13 antibody.
Thus, the ordinarily skilled artisan would consider determining if any given antibody has “the specificity of the antibody of claim 18(i)” as recited in 18(iii) to be a highly unpredictable endeavor necessitating far more than routine experimentation.
In view of the above, undue experimentation would be required to practice the invention commensurate with the breadth of the claims based on the disclosure of the instant specification and the knowledge in the prior art.
Claims 18, 20, 21, 23 and 24 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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding, binding to a certain epitope), claiming antibodies with specific properties, e.g., CLDN18.2 binding, can result in a claim that does not meet written description even when the antigen(s) bound by the antibody is known, because antibodies with those properties have not been adequately described. See Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Along these same lines, as more recent Federal Circuit decision, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describes how when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself not just a description of the sequence to which the antibody binds. Amgen, 872 F.3d at 1378-79.
The importance of this court decision was expounded upon by Robert W. Bahr, Deputy Commissioner for Patent Examination Policy in a memorandum clarifying the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) as it relates to claims drawn to antibodies (see Memorandum of February 22, 2018, 2 pages, available at https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf). Bahr’s memo describes how the so-called “newly characterized antigen” test, which was based on an example in previously issued USPTO training materials and had been used in the past for determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody, is defunct. The Memorandum explains that USPTO personnel should continue to follow the relevant sections of the MPEP pertaining to the written description requirement of 35 U.S.C. § 112(a), except insofar as the MPEP indicates that disclosure of a fully characterized antigen may provide written descriptive support of an antibody to that antigen.
In particular, MPEP § 2163 instructs that the “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice…reduction to drawings…or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus…See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
Note well: even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
In the instant case, the claims are drawn to:
“[t]he method of claim 1, wherein the anti-CLDN18.2 antibody is an antibody selected from the group consisting of: (i) an antibody produced by and/or obtainable from a clone deposited under the accession no. DSM ACC2737, DSM ACC2738, DSM ACC2739, DSM ACC2740, DSM ACC2741, DSM ACC2742, DSM ACC2743, DSM ACC2745, DSM ACC2746, DSM ACC2747, DSM ACC2748, DSM ACC2808, DSM ACC2809, or DSM ACC2810…(iii) an antibody having the specificity of the antibody under (i)…. (claim 18); and drawn to,
the method of claim 1, wherein the anti-CLDN18.2 antibody comprises sequence defined heavy and light chain variable domains, including “a functional variant thereof, or a fragment of the amino acid sequence or functional variant” (claims 20, 21, 23 and 24).
With respect to the antibodies of the first bullet above, at page 69-70 bridging paragraph the specification discloses (emphasis added):
“Two binding molecules have the “same specificity” if they bind to the same antigen and to the same epitope. Whether a molecule to be tested recognizes the same epitope as a certain binding molecule, i.e., the binding molecules bind to the same epitope, can be tested by different methods known to the skilled person. The competition of the binding molecules such as antibodies for the same epitope may provide an indication for the binding molecules binding to the same epitope. The competition between the binding molecules can be detected by a cross-blocking assay. For example, a competitive ELISA assay may be used as a cross-blocking assay. For example, target antigen may be coated on the wells of a microtiter plate and antigen binding antibody and candidate competing test antibody may be added. The amount of the antigen binding antibody bound to the antigen in the well indirectly correlates with the binding ability of the candidate competing test antibody that competes therewith for binding to the same epitope. Specifically, the larger the affinity of the candidate competing test antibody is for the same epitope, the smaller the amount of the antigen binding antibody bound to the antigen-coated well. The amount of the antigen binding antibody bound to the well can be measured by labeling the antibody with detectable or measurable labeling substances.”
Further to the above, at page 27, 1st and 2nd full paragraphs (emphasis added), the specification further instructs:
“In a preferred embodiment, an antibody that is an immune checkpoint inhibitor, is an isolated antibody. The antibody that is an immune checkpoint inhibitor or the antigen-binding fragment thereof according to the present disclosure may also be an antibody that cross-competes for antigen binding with any known immune checkpoint inhibitor antibody. In certain embodiments, an immune checkpoint inhibitor antibody cross-competes with one or more of the immune checkpoint inhibitor antibodies described herein. The ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies may bind to the same epitope region of the antigen or when binding to another epitope sterically hinder the binding of known immune checkpoint inhibitor antibodies to that particular epitope region. These cross- competing antibodies may have functional properties very similar to those they are cross- competing with as they are expected to block binding of the immune checkpoint to its ligand either by binding to the same epitope or by sterically hindering the binding of the ligand. Cross-competing antibodies can be readily identified based on their ability to cross-compete with one or more of known antibodies in standard binding assays such as Surface Plasmon Resonance analysis, ELISA assays or flow cytometry (see, e.g., WO 2013/173223).
In certain embodiments, antibodies or antigen binding fragments thereof that cross-compete for binding to a given antigen with or bind to the same epitope region of a given antigen as, one or more known antibodies are monoclonal antibodies. For administration to human patients, these cross-competing antibodies can be chimeric antibodies, or humanized or human antibodies. Such chimeric, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.”
In view of the above, part (iii) of claim 18, given its broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art, would be understood to refers to the genus of antibodies that “bind to the same antigen and to the same epitope,” which would necessarily not include, e.g., those antibodies that “cross compete” with the antibodies of claim 18(i) by binding to another epitope and sterically hindering the binding of the antibodies of claim 18(i) to their particular “epitope.”
At page 75, 1st paragraph, the specification further discloses (emphasis added):
“The term “functional variant”, as used herein, refers to a variant molecule or sequence that comprises an amino acid sequence that is altered by one or more amino acids compared to the amino acid sequence of the parent molecule or sequence and that is still capable of fulfilling one or more of the functions of the parent molecule or sequence, e.g., binding to a target molecule or contributing to binding to a target molecule. If the parent molecule or sequence is an antibody molecule or sequence, the alteration is preferably not in the variable regions of the antibody, more preferably not in the CDR regions of the antibody. In one embodiment, a functional variant either alone or in combination with other elements competes for binding to a target molecule with the parent molecule or sequence. In other words, the modifications in the amino acid sequence of the parent molecule or sequence do not significantly affect or alter the binding characteristics of the molecule or sequence. In different embodiments, binding of the functional variant may be reduced but still significantly present, e.g., binding of the functional variant may be at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the parent molecule or sequence. However, in other embodiments, binding of the functional variant may be enhanced compared to the parent molecule or sequence.”
Thus, the breadth of the claimed genus is enormous encompassing, on the one hand all antibodies that bind the same epitope as the antibodies recited in claim 18(i) and on the other hand the genus of antibodies having any number of amino acid substitutions, insertions or deletions to the CDR domains, be they radical or conservative.
However, simply reciting a structure, e.g., anti-CLDN18.2 antibodies comprising certain sequence specified Vh OR Vl variable domains having any number of amino acid substitutions in their CDR domains, be they radical or conservative, and its function, i.e., binding to CLDN18.2, provides insufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995).
Conservation of the CDR residues is of particular importance because any number of Vh and VL CDR residues are expected, a priori, to contribute to antigen binding and yet the instant specification and the knowledge in the art do not establish which residues of the claimed CLDN18.2 binding antibodies are structurally essential to antigen binding versus those that are tolerant to change, and to what degree, i.e., conservative or radical.
To illustrate this point, consider Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28, cited herewith) which teaches “[t]he specificity and affinity of an antibody for its cognate antigen is determined by the sequence and structure of the variable fragment (Fv): a heterodimer consisting of the N-terminal domains of the heavy and light chains. Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.” (see, page 416, column bridging paragraph, emphasis added).
Vajdos goes on to teach that "[b]y analyzing panels of point mutants, a detailed map of the
binding energetics can be obtained, but the process can be very laborious because individual
mutant proteins must be made and analyzed separately. In particular, a comprehensive analysis
of an antigen binding site would ideally encompass all CDR residues, and this would require the
analysis of dozens or even hundreds of point mutants." (see page 416, right column, first
paragraph). Vajdos solution to this dilemma was to make use of a shotgun scanning mutagenesis
which "uses phage displayed libraries of protein mutants constructed using degenerate codons
with restricted diversity." While this method of making libraries of mutants representative of the
potential antigen binding CDR residues was an improvement over previous strategies as taught
by Vajdos, it nonetheless required extensive experimentation to comprehensively scan the
potential CDR sequence space (see page 416, right column, 2nd paragraph and pages 425-427,
Materials and Methods.)
Furthermore, even after performing this comprehensive scanning mutagenesis of all CDR
residues from the particular anti-ErB2 antibody under study, Vajdos would still not have been
able to say which CDR residues were actually involved in antigen binding, and which were
involved in stabilizing the secondary and tertiary structure of the CDRs within the context of the
heavy and light chains as a whole, without the structure of the unbound antigen-binding site of
the antibody to aid in their analysis (see, in particular, Discussion, pages 422-425).
Rather, Vajdos needed to perform not only a comprehensive shotgun scanning mutagenesis of all
CDR residues of the antibody under study, but also needed a structure of the unbound antigen binding site in hand to gain a sufficient understanding of the contribution of each CDR to
antigen-binding to adequately predict which CDR residues can be changed, and to what extent,
or in what context of additional compensatory mutations in other regions of the antibody.
Moreover, given an amino acid substitution that ablated binding, without the crystal structure in
hand, still further experimentation would have been required to determine the flexibility in this
particular residue, i.e., it's general tolerance or intolerance to change.
As yet another example to illustrate the sensitivity of some antibodies to changes in their CDR residues, especially CDR3, consider the teachings of Bedouelle et al. (FEBS J. 2006 Jan;273(1):34-46, cited herewith). While Bedouelle did not comprehensively scan all the CDR residues of their antibody using a combination of alanine and homologous substitutions as shown in Vajdos, Bedouelle did examine the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a >100 fold drop in binding affinity (see Table 1). As described by Bedouelle, some of these loss of function mutations were hypothesized to have a direct effect on antigen binding while others were hypothesized to indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section). Thus, the teachings of Bedouelle provide further illustration of the unpredictability of making mutations within the CDR region of an antibody.
Notably, while the teachings of Vajdos and Bedouelle demonstrate the unpredictable effects of even single amino acid changes on antibody:antigen binding, there is an additional level of unpredictability in the art associated with making multiple changes in any given CDR(s).
In particular, even in those instances where one can show certain residues of a given CDR are generally tolerant of single amino acid changes, this does not necessarily mean a combination of single amino acid changes, even to the same residues shown to tolerate change when mutated in isolation, will be tolerated. As an example consider Brown et al. (J Immunol. 1996 May 1;156(9):3285-91, cited herewith) which describes how the Vh CDR2 in a particular antibody was generally tolerant of single amino acid changes; however, the antibody lost binding upon the introduction of pairs of single amino changes in the same region (see, in particular Tables I and II and column bridging paragraph on page 3290).
Additionally, as emphasized by the teachings of Colman (Research in Immunology, 145:33-36, 1994, cited herewith) the type of CDR amino acid substitution, i.e., conservative vs. non-conservative, is not necessarily a good predictor of antigen binding: "[t]he above examples paint a confusing picture of the specificity of antibody-antigen interaction. In one structural context, a very conservative substitution may abolish binding; in another, a nonconservative substitution may have very little effect on the binding affinity.” (see pg. 35, top of left column). Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79: 1979-1983, March 1982, cited herewith) provides another example of how even a conservative change to a single amino acid residue in a CDR region of an antibody can ablate antigen binding (see, for example, Abstract).
Given the above, the teachings of the instant specification and/or the knowledge in the prior art were insufficient to establish possession of the breadth of variants encompassed by the instant claims which will preserve CLDN18.2-binding to the extent necessary to, e.g., allow the anti-CLDN18.2 antibody to bind to and mediate ADCC- and/or CDC-dependent lysis of, for example, gastric cancers having low level CLDN18.2 expression (see, Dottermusch et al., Virchows Archiv (2019) 475:563–571, and supplemental pages 1-4, cited herewith, at page 570, col. bridging section entitled, “CLDN18.2 expression is decreased in gastric cancer”).
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of CLDN18.2 -binding antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of methods of treatment that make use of the claimed genus of antibodies.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 3, 4, 6, 10, 12, 14, 16, 18-25, 27, 28 and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 5, 7, 9-17, 20, 22, 24-27 and 32-42 of copending Application No. 17/632157, in view of Sahin et al. (20180326059, cited herewith) and “BMS” (BMS Press Release January 4, 2021, “European Medicines Agency Validates Bristol Myers Squibb’s Application for Opdivo (nivolumab) Combined with Chemotherapy as First-Line Treatment in Metastatic Gastric Cancer, Gastroesophageal Junction Cancer and Esophageal Adenocarcinoma, pages 1- 17)(both cited herewith).
The reference claims are drawn to methods for treating cancer in a patient, comprising administering to the patient an anti-CLDN18.2 antibody and an immune checkpoint inhibitor, wherein the method inhibits tumor growth in the patient, said methods encompassing many element of the instant claims such as:
Reference claim 5:
“The method of claim 1, wherein the immune checkpoint inhibitor is selected from an anti-PD-1 antibody, and an anti-PD-LI antibody”
Reference claim 7:
“The method of claim 5, wherein the anti-PD-1 antibody is nivolumab (OPDIVO; BMS- 936558), pembrolizumab (KEYTRUDA; MK-3475), pidilizumab (CT-Ol1), cemiplimab (LIBTAYO, REGN2810), spartalizumab (PDR001), MEDI0680 (AMP- 514), dostarlimab (TSR- 042), cetrelimab (JNJ 63723283), toripalimab (JS001), AMP-224 (GSK- 2661380), PF- 06801591, tislelizumab (BGB-A317), ABBV-181, BI 754091, or SHR-1210.”
Reference claim 9:
“The method of claim 5, wherein the anti-PD-LI antibody is atezolizumab (TECENTRIQ; RG7446; MPDL3280A; R05541267), durvalumab (MEDI4736), BMS-936559, avelumab (bavencio), lodapolimab (LY3300054), CX-072 (Proclaim-CX-072), FAZ053, KN035, or MDX-1105.”
Reference claim 15:
“The method of claim 1, wherein the anti-CLDN18.2 antibody is an antibody selected from the group consisting of: (i) an antibody produced by and/or obtainable from a clone deposited under the accession no. DSM ACC2737, DSM ACC2738, DSM ACC2739, DSM ACC2740, DSM ACC2741, DSM ACC2742, DSM ACC2743, DSM ACC2745, DSM ACC2746, DSM ACC2747, DSM ACC2748, DSM ACC2808, DSM ACC2809, or DSM ACC2810, (ii) an antibody which is a chimerized or humanized form of the antibody under (i), (iii) an antibody having the specificity of the antibody under (i), and (iv) an antibody comprising the antigen binding portion or antigen binding site, in particular the variable region, of the antibody under (i) and preferably having the specificity of the antibody under (i).”
Reference claim 16:
“The method of claim 1, wherein the anti-CLDN18.2 antibody comprises a heavy chain variable region CDR1 comprising the sequence of positions 45- Page 3 52 of the sequence set forth in SEQ ID NO: 17, a heavy chain variable region CDR2 comprising the sequence of positions 70-77 of the sequence set forth in SEQ ID NO: 17, a heavy chain variable region CDR3 comprising the sequence of positions 116-126 of the sequence set forth in SEQ ID NO: 17, a light chain variable region CDR1 comprising the sequence of positions 47-58 of the sequence set forth in SEQ ID NO: 24, a light chain variable region CDR2 comprising the sequence of positions 76-78 of the sequence set forth in SEQ ID NO: 24, and a light chain variable region CDR3 comprising the sequence of positions 115-123 of the sequence set forth in SEQ ID NO: 24.”
Etc.
However, the reference claims do not further include administering a platinum compound and a fluoropyrimidine compound or precursor thereof.
At para 0012 Sahin teaches:
“…we present data demonstrating that chemotherapeutic agents can stabilize or increase expression of CLDN18.2 on the surface of cancer cells resulting in an enhanced drugability of CLDN18.2 by an anti-CLDN18.2 antibody such as IMAB362. A synergistic effect of an anti-CLDN18.2 antibody such as IMAB362 with particular chemotherapeutic regimens, in particular chemotherapeutic regimens used for gastric cancer treatment or treatment of human solid cancers was observed. Human cancer cells pre-treated with chemotherapy are more susceptible to antibody-induced target-specific killing. In mouse tumor models, tumor control with an anti-CLDN18.2 antibody plus chemotherapy is superior to that with an anti-CLDN18.2 antibody as single agent.”
At para 0017 Sahin further teaches:
“[t]he agent stabilizing or increasing expression of CLDN18.2 may be a cytotoxic and/or cytostatic agent. In one embodiment, the agent stabilizing or increasing expression of CLDN18.2 comprises an agent which induces a cell cycle arrest or an accumulation of cells in one or more phases of the cell cycle, preferably in one or more phases of the cell cycle other than the G1-phase. The agent stabilizing or increasing expression of CLDN18.2 may comprise an agent selected from the group consisting of anthracyclines, platinum compounds, nucleoside analogs, taxanes, and camptothecin analogs, or prodrugs thereof, and combinations thereof. The agent stabilizing or increasing expression of CLDN18.2 may comprise an agent selected from the group consisting of epirubicin, oxaliplatin, cisplatin, 5-fluorouracil or prodrugs thereof such as capecitabine, docetaxel, irinotecan, and combinations thereof. The agent stabilizing or increasing expression of CLDN18.2 may comprise a combination of oxaliplatin and 5-fluorouracil or prodrugs thereof, a combination of cisplatin and 5-fluorouracil or prodrugs thereof, a combination of at least one anthracycline and oxaliplatin, a combination of at least one anthracycline and cisplatin, a combination of at least one anthracycline and 5-fluorouracil or prodrugs thereof, a combination of at least one taxane and oxaliplatin, a combination of at least one taxane and cisplatin, a combination of at least one taxane and 5-fluorouracil or prodrugs thereof, or a combination of at least one camptothecin analog and 5-fluorouracil or prodrugs thereof. The agent stabilizing or increasing expression of CLDN18.2 may be an agent inducing immunogenic cell death. The agent inducing immunogenic cell death may comprise an agent selected from the group consisting of anthracyclines, oxaliplatin and combinations thereof. The agent stabilizing or increasing expression of CLDN18.2 may comprise a combination of epirubicin and oxaliplatin. In one embodiment, the method of the invention comprises administering at least one anthracycline, at least one platinum compound and at least one of 5-fluorouracil and prodrugs thereof. The anthracycline may be selected from the group consisting of epirubicin, doxorubicin, daunorubicin, idarubicin and valrubicin. Preferably, the anthracycline is epirubicin. The platinum compound may selected from the group consisting of oxaliplatin and cisplatin. The nucleoside analog may be selected from the group consisting of 5-fluorouracil and prodrugs thereof. The taxane may be selected from the group consisting of docetaxel and paclitaxel. The camptothecin analog may be selected from the group consisting of irinotecan and topotecan. In one embodiment, the method of the invention comprises administering (i) epirubicin, oxaliplatin and 5-fluorouracil, (ii) epirubicin, oxaliplatin and capecitabine, (iii) epirubicin, cisplatin and 5-fluorouracil, (iv) epirubicin, cisplatin and capecitabine, or (v) folinic acid, oxaliplatin and 5-fluorouracil.”
BMS taught “…the European Medicines Agency (EMA) validated its Type II Variation Marketing Authorization Application (MAA) for Opdivo (nivolumab) in combination with fluoropyrimidine- and platinum-based combination chemotherapy for the first-line treatment of adult patients with advanced or metastatic gastric cancer (GC), gastroesophageal junction (GEJ) cancer or esophageal adenocarcinoma (EAC)…. The filing is based on results from the pivotal Phase 3 CheckMate -649 trial, in which first-line treatment with Opdivo plus leucovorin, 5-fluorouracil and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CapeOX) was compared to treatment with chemotherapy alone. Results showed a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) in patients with unresectable advanced or metastatic GC, GEJ cancer or EAC whose tumors express PD-L1 with a combined positive score (CPS) ≥ 5 (the primary endpoints of the study). The statistically significant OS benefit shown with Opdivo plus chemotherapy was also observed in PD-L1 positive patients with CPS ≥ 1 and in the all-randomized population. The safety profile observed for Opdivo plus chemotherapy in the CheckMate -649 trial was consistent with the known safety profiles of the individual treatments.” (see page 1).
Given the reference claims and the teachings of Sahin and BMS, it would have been obvious to one of ordinary skill in the art to add 5-fluorouracil and oxaliplatin (FOLFOX) to the methods of treatment recited in the reference claims since, as described by Sahin, such chemotherapeutic agents were expected to stabilize or increase expression of CLDN18.2 on the surface of cancer cells resulting in an enhanced drugability of CLDN18.2 by an anti-CLDN18.2 antibody such as IMAB362, and as further described by BMS, the combination of the anti-PD-1 antibody nivolumab and the chemotherapeutic treatment of 5-fluorouracil and oxaliplatin (FOLFOX) was known to safely and effectively treat various types of gastric cancers.
Note in this regard that as pointed out in MPEP 2144.06 (I), "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose…. [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). This rationale is also consistent with KSR Exemplary Rationale (A) (see MPEP 2141 (III)): Combining prior art elements (combining administration of anti-CLDN18.2 antibody and a checkpoint inhibitor to treat a CLDN18.2-expressing cancer with administration of a checkpoint inhibitor and chemotherapeutic agents to also treat a CLDN18.2-expressing cancer).
This is a provisional nonstatutory double patenting rejection.
No claims are allowed.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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