DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
Claims 2-53 have been canceled as requested in the amendment filed on 31 January 2024. Following the amendment, claim 1 is pending in the instant application, and under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a continuation of US Application No. 17/174,019 filed on 11 February 2021; US Application No. 15/399,118 filed 5 January 2017; US Application No. PCT/US2015/04058 filed 15 July 2015 and claiming the benefit of US Provisional Application No. 62/024,988 15 July 2014.
Claim 1 has an earliest effective filing date of 15 July 2014.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/12/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
Claim 1 is 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.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Claim 1 recites, “a PD-1 axis binding antagonist and a MEK inhibitor”. Regarding the “PD-1 axis binding antagonist” the specification teaches a long list of potential antagonists (paragraphs [0014] and [0138] through [0175]) but the claims also encompass anti-PD-1 antagonist antibodies and the specification discloses only a few specific species: comprising the heavy chain variable region of SEQ ID NO:24 or 28 and the light chain variable region of SEQ ID NO:21; a heavy chain comprising SEQ ID NO: 26 and a light chain comprising SEQ ID NO: 27. Regarding the MEK inhibitor of the claims, paragraphs [0014] and [0176] through [0193] and Table 1 of the specification also teaches a species within the genus. However, the claims do not require that the antagonist or inhibitor possess any particular structure, nor does the claim provide a distinguishing feature such that a person having ordinary skill in the art would be able to at once envision what antagonists and inhibitors were encompassed by the invention. Therefore, the claims are drawn to genera of molecules.
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 (see MPEP 2163(II)(3)(a)( i)(A), reduction to drawings MPEP 2163(II)(3)(a) (i)(B), 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 MPEP 2163(II)(3)(a) (i)(C). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
In the instant case, the only factor present in the claim is a recitation of requisite activity (a PD-1 axis binding antagonist; MEK inhibitor). There is not even identification of any particular portion of a structure that must be conserved for activity. As stated above, the specification provides examples of each genus encompassed, however this listing of species is no representative of the genus as a whole. Nor is there adequate written description of the distinguishing identifying characteristics of the genus as a whole.
The claims encompass antagonist/inhibitor antibodies and yet the specification discloses only one PD-1 axis binding antagonist antibody (see sequences above). In Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), the court stated that disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties). See MPEP 2163.II.A.3(a). While the claims in Amgen were directed to an antibody per se, TC1600-specific training (Examples 5-7 of the Office' s training dated 6/3/19) requires examiners to apply this case law to method claims comprising an antibody. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Thus, in view of the Amgen decision, the instant claims fail to meet the requirements for disclosure because, while the claims read upon PD-1 axis binding antagonist antibodies and MEK inhibitor antibodies, the disclosure teaches only one species of a PD-1 axis binding antagonist antibody.
Accordingly, in the absence of sufficient recitation of distinguishing characteristics of the molecules within each genus claimed, or recitation of a representative number of species within each genus claimed, then the specification does not provide adequate written description of the claimed genera, and Claim 1 is rejected for failing to meet the written description requirement of 35 U.S.C. 112(a).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claim 1 is 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 combined administration of Cobimetinib/GDC-0973 plus the anti-PDL1 as a 2nd line therapy for Vemurafenib-progressing melanoma tumors (the sole example paragraphs [0211] and [0223]), does not reasonably provide enablement for the method comprising any other PD-1 axis binding antagonist or any other MEK inhibitor, wherein the cancer is resistant to any other B-raf antagonist. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. In addition, when analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be “given their broadest reasonable interpretation consistent with the specification.” See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
As such, the broadest reasonable interpretation of the claimed method is that it provides treatment for treating or delaying the progression of any cancer that is resistant to any B-raf antagonist comprising administering to the individual an effective amount of any PD-1 axis binding antagonist and any MEK inhibitor. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
As stated above, the scope of the genus of PD-1 antagonist and MEK inhibitors is vast, encompassing a vast array of molecules listed in the specification. However, in contrast to what is encompassed by the claims, what is disclosed about the invention is narrow. The specification, while being enabling for combined administration of Cobimetinib/GDC-0973 plus an anti-PDL1 as a 2nd line therapy for Vemurafenib-progressing tumors (the sole example paragraphs [0211] and [0223]). First, the literature teaches that not all cancers are BRAF inhibitor resistant. The following prior art teaches about 50% of melanomas have the presence of BRAF mutations (Villanueva et al., Cancer Res. 71(23): 7137-7140, December 2011). Villanueva et al. teach targeting BRAF using RAF-selective inhibitors results in remarkable tumor shrinkage in BRAFV600E melanomas, and other activating mutations such as V600K/D/R also appear responsive to BRAF inhibitors. Patients with BRAFV600E melanomas were treated with the RAF inhibitor vemurafenib (PLX4032/RG7204) 48% had confirmed objective response rates and an increased overall survival (84%) compared to those treated with dacarbazine (64%) at 6 months. Despite these encouraging results, responses to RAF inhibitors are transient, resistance to these compounds develops, and tumors invariably recur. Understanding the molecular mechanisms of resistance to RAF inhibitors is now critical to maximize their clinical success, achieve complete durable responses, and improve patient outcomes (pg. 1).
Methods for treating melanoma comprising PD-1 inhibition were well-established in the art before the effective filing date of the application (Hamid et al., N Engl J Med 2013;369:134-44). Additionally, Maecker et al. (WO2013019906, published on Feb 2013) teaches a method of combinational therapy for treating melanoma with anti-PD-L1 antibody and MEK inhibitor, wherein the MEK inhibitor is GDC-0973 and PD-L1 antibody.
The claims, however, read upon the method comprising a vast array of PD-1 inhibitors and MEK inhibitors for the treatment of any cancer. The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentech, Inc, v. Novo Nordisk, 42 USPQ 2d 1001, (CAFC 1997), the court held that:
"[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" and that "[t]ossing out the mere germ of an idea does not constitute enabling disclosure". The court further stated that "when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art", "[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement".
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method, commensurate in scope with the breadth of the claims, without making a substantial inventive contribution. Given that the nature of the invention is in vivo treatment, a person having ordinary skill in the art would have to perform multiple further in vivo experiments, comprising various PD-1 antagonists and various MEK inhibitors, in animal models that are predictive of treatment in various cancers that demonstrate resistance to a B-raf antagonist. This amount of experimentation required for enabling guidance, commensurate in scope with the breadth of the claims, goes beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of success. Therefore, Claim 1 is rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
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.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maecker et al (WO2013019906, published on Feb 2013, as evidenced by sequence alignment and Bucheit et al (Biochemical Pharmacology 87:381-389, Published online Nov 28, 2013).
The instant specification discloses the PD-L1 antibody, MPDL3280A, YW243.55.S70 and Atezolizumab as all have the same antigen binding regions and/or 6 CDRs.
Regarding Claim 1, Maecker et al teach a method of combinational therapy for treating melanoma with anti-PD-L1 antibody and MEK inhibitor, wherein the MEK inhibitor is Cobimetinib/GDC-0973 ([0016] and claim 29) and PD-L1 antibody comprises the identical 6 CDRS (SEQ ID NO: 15, 16, 3 and 17-19) and heavy and light variable regions (SEQ ID NO: 24 and 21, claims 19 ) as the PD-L1 antibody of the instant application (see pgs. 42-44 and alignment below). Maecker et al teach that melanoma being treated has wild type or mutations in KRAS and BRAF, such as V600E [0010, 0016 and 0121], Maecker et al also state that the MEK inhibitor is more selective against BRAF V600E mutation [0210] and combinational therapy enhances the anti-tumor activity of anti-PD-L1 antibody in vivo model as compared to the treatment with either of the inhibitor alone ([0026+ and figure 8+, 13). Maecker et al also teach that the human melanoma have been treating with BRAF inhibitor GDC-0879 as compared to MEK inhibitor and suggest that MEK inhibitor is more effective than BRAF inhibitor (figure 2, [0406]).
CC PN WO2013019906-A1.
CC PD 07-FEB-2013.
CC PF 01-AUG-2012; 2012WO-US049233.
PR 01-AUG-2011; 2011US-0574406P.
CC PA (GETH ) GENENTECH INC.
CC PA (HOFF ) HOFFMANN LA ROCHE&CO AG F.
CC PI Maecker H, Irving B;
CC PT Treating or delaying progression of cancer e.g. melanoma and pancreatic cancer, comprises administering a programmed cell death protein 1 axis binding antagonist e.g. pidilizumab, and a mitogen-activated protein
CC PS Claim 20; SEQ ID NO 24; 127pp; English.
Fusion SEQ ID Nos: 15-16-3:
DT 11-APR-2013 (first entry)
DE Anti-PD-L1 antibody heavy chain variable region, SEQ ID 24.
SQ Sequence 118 AA;
Qy 1 GFTFSDSWIH-------------AWISPYGGSTYYADSVKG------------------- 28
Qy 29 -------------RHWPGGFDY 37
Db 26 GFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNS 85
Db 86 LRAEDTAVYYCARRHWPGGFDY 107
Fusion SEQ ID Nos: 17-18-19:
Anti-PD-L1 antibody light chain variable region, SEQ ID 21.
SQ Sequence 108 AA;
Query Match 81.6%; Score 109.3; DB 20; Length 108;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RASQDVSTAVA---------------SASFLYS--------------------------- 18
Qy 19 -----QQYLYHPAT 27
Db 24 RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF 83
Db 84 ATYYCQQYLYHPAT 97
Thus, Maecker et al teach the same materials (both PD-L1 antibody and MEK inhibitor) used for treating melanoma, with the same method step, administering. In Maecker’s method, melanoma patients include those having Braf (B-raf) mutation at V600E [0016 and 0121], who would and could be diagnosed as resistant to Braf antagonist if the patient once being treated with Braf antagonist, which evidenced by Bucheit et al, who teach majority of melanoma patients having mutation V600E, which increases Braf kinase and its pathway activity and uncontrolled proliferation (page 381, right col and fig 1-a). Bucheit et al teach the patients selected first treatment with small molecule inhibitors of Braf including Vemurafenib or Dabrafenib (bridging page 382-3, section 4), but developed resistance after short period of treatment (fig 1-b-d, section 5).
Double Patenting
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 is rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 9,724,413 in view of Bucheit et al (Biochemical Pharmacology 87:381-389, Published online Nov 28, 2013) and modified as follows.
Claim 1 is drawn to a method of treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a MEK inhibitor, wherein the individual has cancer or is at risk of developing cancer that is resistant to a B-raf antagonist.
The claims of Patent ‘413 are drawn to a method of combinational therapy for treating melanoma with anti-PD-L1 antibody and MEK inhibitor GDC-0973, wherein the anti-PD-L1 antibody having the CDRs and variable region of SEQ ID NO: 24 and 21, which is identical to the antibody of the specification (see instant specification pgs.42-44 and alignment below) wherein the cancer patients contain wild type of Braf and KRAS and mutations of Braf at V600 including V660E and mutations of KRAS protein mutation at V600E (claim 9).
The claims of the ‘413 Patent are a species of the generis claim in the present application. MPEP 2131.02 states: “A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus.” Therefore, the Patented claims anticipate the claim of the instant application.
The Bucheit reference is relied upon as teaching a majority of melanoma patients having mutation V600E, have increased Braf kinase and its pathway activity and uncontrolled proliferation (page 381, right col and fig 1-a). Bucheit et al teach the patients selected first treatment with small molecule inhibitors of Braf including Vemurafenib or Dabrafenib (bridging page 382-3, section 4), but developed resistance after short period of treatment (fig 1-b-d, section 5).
The anti-PD-L1 antibody has the identical CDRs and variable region as instantly claimed antibody as evidenced by sequence alignment set forth below.
Fusion SEQ ID Nos: 15-16-3:
DT 11-APR-2013 (first entry)
DE Anti-PD-L1 antibody heavy chain variable region, SEQ ID 24.
SQ Sequence 118 AA;
Qy 1 GFTFSDSWIH-------------AWISPYGGSTYYADSVKG------------------- 28
Qy 29 -------------RHWPGGFDY 37
Db GFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNS 85
Db 86 LRAEDTAVYYCARRHWPGGFDY 107
Fusion SEQ ID Nos: 17-18-19:
Anti-PD-L1 antibody light chain variable region, SEQ ID 21.
SQ Sequence 108 AA;
Qy 1 RASQDVSTAVA---------------SASFLYS--------------------------- 18
Qy 19 -----QQYLYHPAT 27
Db 24 RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDF 83
Db 84 ATYYCQQYLYHPAT 97
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/Examiner, Art Unit 1675
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