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
Claim Status
The claims filed March 14, 2023 have been received and entered.
Claims 1-32 are pending.
Claims 20-22 and 26-32 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
Claims 1-19 and 23-25 are under examination.
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 371 of PCT/US2021/050143 filed on September 14, 2021 which claims the benefit of U.S. Provisional Application 63/078,485 filed on September 15, 2020.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on July 19, 2024, September 5, 2024, and September 30, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 6-7, 13-14, and 18-19 are objected to because of the following informalities:
Claims 6-7, 13-14, and 18-19 recite SEQ ID NOs with and without a space between the colon and the sequence number. For example, claim 6 recites SEQ ID NO:4 and SEQ ID NO: 9. For consistency with the other recited amino acid sequences, the SEQ ID NOs should have a space as in SEQ ID NO: 9.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 15-16 and 23-25 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claims 15-16 and 23-25 recite “Ab6 variant” or “Ab6 antibody”. The instant specification defines Ab6 as a “monoclonal antibody that consists of two heavy chain and two light chain sequences of SEQ ID NO: 23 and SEQ ID NO: 22, respectively” [pg. 6, lines 28-29]. The instant specification further defines an Ab6 variant as “substantially the same as Ab6 with respect to the following properties: binding affinity to human LAG3 and ability to block the binding of human LAG3 to human MHC Class I” [pg. 7, lines 6-8]. However, it is unclear whether Ab6, or the Ab6 variant, is limited to only the heavy chain and light chain sequences recited in the disclosure, or does it allow for other features (e.g., different VH or VL sequences, glycosylated sequences, etc.). As such, a person skilled in the art could not determine when Ab6 stops being the anti-LAG-3 antibody Ab6 or variant thereof as recited in the instant claims.
Claim Rejections - 35 USC § 112(a)
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.
Claim 1 is rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
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 MPEP § 2163.
Claim 1 is drawn to a PD-1 antagonist and a LAG3 antagonist. However, the term antagonist does not convey any information about the structural features a given compound must exhibit in order to antagonize. Further, the instant specification defines a LAG3 antagonist as “any chemical compound or biological molecule that blocks binding of LAG3 expressed on an immune cell (T cell, Tregs, or NK cell etc.) to MHC Class II molecules [pg. 15, lines 21-22]; and defines a PD-1 antagonist as “any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1 [pg. 17, lines 17-19]. Therefore, the claim encompasses a large genus of molecules with the function of antagonizing PD-1 or LAG3.
The state of the art is such that the production of inhibitory molecules is extremely complex and requires a deep understanding of protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system. The development of candidate inhibitors involves a complex process of evaluation that includes identification of the physical and chemical properties of the inhibitor. In regard to PD-1 antagonists in particular, the art recognizes that the function of
PD-1 inhibitors is extremely complex and unpredictable and the binding sites and mechanism for different inhibitors is diverse. The most common mechanism of action of inhibitors targeting PD-1/PD-L1 is to inhibit the binding of PD-1 and PD-L1 by occupying their extracellular interaction sites [Chen et al, 2019; pg. 381]. Chen teaches various inhibitors targeting the PD-1/PD-L1 pathway including monoclonal antibodies (e.g., pembrolizumab, nivolumab, durvalumab) which have varying efficacy accompanied by low bioavailability, inability to reach intracellular targets, and propensity to cause immune-related adverse events (irAEs) [pg. 380, col. 1]. Chen also teaches peptides and peptidomimetics as inhibitors of the PD-1/PD-L1 pathway with a shorter half-life to overcome the pharmacokinetic limitations of current antibody modulators and better control irAEs [pg. 385, col 1], and small molecules containing sulfamonomethoxine and sulfamethizole derivatives, however, insufficient target structure information hinders the development of small molecule inhibitors [pg. 388, col. 1].
Similarly, the LAG3 antagonists comprise different molecules, including monoclonal antibodies and soluble dimeric recombinant proteins, which have different binding targets and pharmacokinetic properties [Andrews et al., 2017].
Thus, the claim encompasses a broad genus of structurally different antagonists, with different structures that bind to different epitopes of PD-1, PD-L1, or LAG3, or those with different affinities or pharmacokinetic properties. However, the specification discloses the structure (i.e., amino acid sequence) of only monoclonal antibodies against PD-1/PD-L1 and LAG3. The instant application has not provided a sufficient description showing possession of the necessary 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 genus of PD-1 or LAG3 antagonists encompassing various structures, specificities and functions. The Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002). In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description’ inquiry, whatever is now claimed." (See Vas-Cath, p. 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath, p. 1116). Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Given the claimed broad class of PD-1 and LAG3 antagonists, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making antibodies with the “limitations above” and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claims 1-19 and 23-25 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for treating colorectal cancer, does not reasonably provide enablement for treating cancer broadly. 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 instant specification is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, see In re Wands, 858 F.2d at 737, 8 USPQ2d at
1404 (Fed. Cir. 1988).
In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or
direction needed to enable the invention is inversely related to the amount of knowledge in the state of
the art as well the predictability in the art.” “The “amount of guidance or direction” refers to that
information in the application, as originally filed, that teaches exactly how to make or use the invention.
The more that is known in the prior art about the nature of the invention, how to make, and how to use
the invention, and the more predictable the art is, the less information needs to be explicitly stated in
the specification. In contrast, if little is known in the prior art about the nature of the invention and the
art is unpredictable, the specification would need more detail as to how to make and use the invention
in order to be enabling” (MPEP § 2164.03). The MPEP further states that physiological activity can be
considered inherently unpredictable. With these teachings in mind, an enabling disclosure,
commensurate in scope with the breadth of the claimed invention, is required.
Claim 1 is drawn to a method for treating cancer in an individual, comprising administering a PD-1 antagonist, a LAG3 antagonist, and lenvatinib.
However, Example 3 of the instant specification [pg. 44] clearly shows that combination therapy with anti-PD-1 + anti-LAG3 + lenvatinib, or anti-LAG3 + lenvatinib, or anti-PD-1 + lenvatinib is ineffective against the treatment of KPC-2838c3 pancreatic tumors which are intrinsically resistant to PD-1. This evidence, substantiated by verifiable facts, clearly raises doubts that the invention can be performed over the entire breadth of the claims. Accordingly, based on the unpredictability of the art and the breadth of the claims, it would require undue experimentation to practice the full scope of the claimed method.
Claims 2-19 and 23-25 are included in the rejection because they depend from or otherwise require all the limitations of the rejected independent claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10 are rejected under 35 U.S.C. 103 as being obvious over Denker et al. (WO 2016/141218; cited on IDS 9/5/2024) (“Denker”), in view of Huang et al. (Oncotarget, 2015; 6:27359-27377) (“Huang”).
The instant claims are drawn to a method of treating cancer in an individual comprising administering to an individual a PD-1 antagonist, a LAG3 antagonist, and lenvatinib or a pharmaceutically acceptable salt thereof, wherein the PD-1 antagonist is a monoclonal antibody comprising the amino acid sequences recited in the instant claims, pembrolizumab, a pembrolizumab variant, or nivolumab.
Denker teaches methods for treating a human individual diagnosed with a cancer, comprising administering to the individual a combination therapy which comprises a PD-antagonist and a multi-RTK inhibitor, wherein the PD-1 antagonist is a monoclonal antibody or an antigen binding fragment thereof, such as pembrolizumab or nivolumab [0011-0012]. Denker teaches the preferred combination of pembrolizumab (or pembrolizumab variant) and lenvatinib or a pharmaceutically acceptable salt thereof for treating cancer [0021, 00181], wherein pembrolizumab inhibits the binding of PD-L1 and PD-L2 to PD-1 [0026].
Example 1 explicitly shows the anti-tumor effect elicited by the administration of lenvatinib when combined with an anti-PD-1 antibody. Specifically, mice harboring lung cancer tumors were administered a daily dose of lenvatinib combined with administration of a mouse anti-PD-1 antibody once a day every three days for a total treatment period of 14 days. In the subcutaneous transplantation model, the combination of lenvatinib and the mouse anti-PD-1 antibody exhibited a significantly higher anti-tumor effect than either administered alone. For example, at day 15, the combination group more than 2.5-fold less tumor volume compared to the control group and the anti-PD-1 group, and over 1.5-fold less tumor volume compared to the lenvatinib group [00203-00206].
Denker further shows the efficacy of the combined treatment in a colon cancer mouse model. Consistent with the experiments conducted in the mouse lung cancer model, the combination of lenvatinib and anti-PD-1 demonstrates a synergistic effect between the two, with the combination of lenvatinib and the anti-mouse-PD-L1 antibody exhibiting a significantly higher antitumor effect than either administered alone. Figure 10 shows a graph of the tumor volume for the control group, lenvatinib or anti-PD-L1 individually, and a combination of lenvatinib and PD-L1. The combination of PD-L1 with lenvatinib exhibited a synergistic effect with respect to the tumor volume. The effect is noticeable at four days post commencement of treatment and very pronounced by days 8 and 11, with mice who received the combined lenvatinib and PD-L1 treatment showing a tumor volume nearly one third the size of the control group's tumor volume on day 11 [00210, 00214-00216].
Figure 6 of Denker teaches the amino acid sequences of the exemplary anti-PD-1 antibody, pembrolizumab. The pembrolizumab heavy and light chain amino acid sequences, SEQ ID NOs: 21 and 22, respectively, are 100% identical to the anti-PD-1 monoclonal antibody amino acid sequences recited in the instant claims [0049].
Denker does not teach the combination treatment further comprises a LAG3 antagonist.
Huang teaches mice with ovarian cancer administered a single blockade therapy of an anti-PD1 or anti-LAG3 antibody did not have a significant benefit from treatment, however, combinatorial blockade with anti-LAG3 and anti-PD1 antibodies significantly delayed the growth of the ovarian tumors.
To further confirm the effects of dual anti-LAG3 and anti-PD1 blockade in delaying tumor growth, Huang tested the antibody blockade in a subcutaneous OVA-expressing lymphoma EG7 tumor model. The anti-PD1 antibody monotherapy demonstrated 50% tumor rejection while anti-LAG3 blockade treatment significantly delayed tumor growth when compared with treatment with an IgG control. However, treatment with dual anti-LAG3/PD1 antibodies resulted in tumor rejection in 100% of the mice [pg. 27362, Fig. 3C].
The teachings of Denker differ from the instant claims in that although a combination therapy comprising administration of an anti-PD-1 antibody + lenvatinib for the treatment of cancer is taught, the composition does not further comprise a LAG3 antagonist. It would have been obvious to one of ordinary skill in the art to modify the synergistic anti-PD-1 + lenvatinib treatment taught by Denker to include an anti-LAG3 antibody given that Huang teaches anti-LAG3 + anti-PD-1 antibody also work in a synergistic manner to reduce tumor burden in various cancers. A skilled artisan would have a reasonable expectation of success in combining the methods because both combination treatments, anti-PD-1 + lenvatinib and anti-PD-1 + anti-LAG3, were effective in reducing tumor growth up to 100% when administered as dual blockade therapies, and it would be expected that administration with anti-PD-1 + anti-LAG3 + lenvatinib would work in a similar synergistic manner to offer an even greater clinical benefit. Accordingly, the combination of prior art references provided a prima facie case of obviousness.
Claims 1, 11-19, and 23-25 are rejected under 35 U.S.C. 103 as being obvious over Denker et al. (WO 2016/141218; cited on IDS 9/5/2024) (“Denker”), in view of Huang et al. (Oncotarget, 2015; 6:27359-27377) (“Huang”) as applied to claims 1-10 above, and in further view of Abraham et al. (WO 2020/096917; cited on IDS 7/19/2024) (“Abraham”).
The instant claims are drawn to a method of treating cancer in an individual comprising administering to an individual a PD-1 antagonist, a LAG3 antagonist, and lenvatinib or a pharmaceutically acceptable salt thereof, wherein the PD-1 antagonist and LAG3 antagonist comprise the amino acid sequences recited in the instant claims. Wherein the PD-1 antagonist is a pembrolizumab variant, and wherein the LAG3 antagonist is monoclonal antibody Ab6. The method comprises administering via intravenous infusion to the individual a composition comprising 200 mg of pembrolizumab and 800 mg of anti-LAG3 antibody Ab6 every three weeks, starting on Day 1, and orally administering 8-20 mg of lenvatinib; or 400 mg pembrolizumab on Day 1 every six weeks and 800 mg Ab6 on Day 1 every three weeks for intravenous infusion, and orally administering daily 8-20 mg of lenvatinib.
The teachings of Denker and Huang are set forth above.
In addition, Denker teaches methods for treating a human individual diagnosed with a cancer, comprising administering to the individual a combination therapy of pembrolizumab and lenvatinib or a pharmaceutically acceptable salt thereof. Lenvatinib is administered orally at a daily dose of 24 mg, 20 mg or 14 mg, and pembrolizumab is administered at a dose of 200 mg every three weeks [0021]. Denker further teaches that lenvatinib can be administered orally once a day starting on Day 1 after completion of pembrolizumab, as 4 mg or 10 mg capsules [00184].
Denker does not teach amino acid sequences for the anti-LAG3 antibody Ab6, or any dosing protocols.
Abraham teaches a combination therapy which comprises administering an anti-PD-1 or anti-PD-L1 antibody and an anti-LAG3 antibody for treatment of cancer. Abraham teaches the specific combination of pembrolizumab, or a variant thereof, which is a monoclonal antibody that inhibits PD-L1 and PD-L2 [pg. 1, lines 5-8], and Ab6, a monoclonal antibody that binds binding of LAG3 with its ligand, MHC II [pg. 2].
Abraham teaches 200 mg pembrolizumab or pembrolizumab variant and 800 mg Ab6 or Ab6 variant are co-administered on Day 1 every three weeks for intravenous infusion [pg. 32, lines 31-32]. Abraham teaches another embodiment wherein 400 mg pembrolizumab or pembrolizumab variant is administered on Day 1 every six weeks and 800 mg Ab6 or Ab6 variant is administered on Day 1 every three weeks for intravenous infusion [pg. 33, lines 24-26].
Abraham teaches the same heavy and light chain amino acid sequences for Ab6, including the 6 CDR regions, as recited in the instant claims [pg. 26-27].
The combined teachings of Denker and Huang differ from those of the instant claims in that although a combination regimen that includes a PD-1 antagonist, a LAG3 antagonist, and lenvatinib for the treatment of cancer is taught, the dosing schedules for the three drugs as recited in the instant claims are not.
It would have been obvious to one of ordinary skill in the art at the time of filing the instant invention to obtain dosing regimens for pembrolizumab, an anti-LAG3 antibody, and lenvatinib from those available in the art. Given that Denker teaches dosing protocols for pembrolizumab and lenvatinib and Abraham teaches a dosing schedule for pembrolizumab and anti-LAG3 antibody Ab6, one would have a reasonable expectation of success of combining these protocols because clinical results show that the double drug combinations (e.g., pembro + Ab6 or pembro + lenvatinib) work synergistically to treat various cancers, and a skilled artisan would expect that this synergistic benefit can be increased by combining all three drugs. As such, the combination of prior art references provided a prima facie case of obviousness.
Double Patenting
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
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.
Claims 1-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, and 34-36 of U.S. Patent No. 12,319,735, in view of over Denker et al. (WO 2016/141218; cited on IDS 9/5/2024) (“Denker”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims are drawn to a composition comprising the identical anti-LAG3 and anti-PD-1 antibodies, Ab6 and pembrolizumab, respectively, as recited in the instant claims.
The instant claims differ from the issued claims in that they do not explicitly teach the Ab6 + pembrolizumab composition further comprises lenvatinib, or that the composition can be used for the treatment of cancer.
The teachings of Denker have been set forth above. Specifically, Denker teaches methods and compositions for treating cancer comprising administering to an individual a combination of an anti-PD-1 antibody and lenvatinib.
It would have been obvious to one of ordinary skill in the art to modify the composition of the issued patent by adding lenvatinib, which has been shown to boost the therapeutic potential of checkpoint inhibitor combination therapies, including anti-PD-1 antibodies as evidenced by Denker. As such, the instant claimed invention is an obvious modification of the claims of the issued patent in view of Denker.
Claims 1 and 23-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, and 34-36 of U.S. Patent No. 12,319,735, in view of Denker et al. (WO 2016/141218; cited on IDS 9/5/2024) (“Denker”) and Abraham et al. (WO 2020/096917; cited on IDS 7/19/2024) (“Abraham”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims are drawn to a composition comprising the identical anti-LAG3 and anti-PD-1 antibodies, Ab6 and pembrolizumab, respectively, as recited in the instant claims.
The instant claims differ from the issued claims in that they do not teach a dosing protocol.
The teachings of Denker and Abraham and have been set forth above.
Specifically, Abraham teaches 200 mg pembrolizumab or pembrolizumab variant and 800 mg Ab6 or Ab6 variant are co-administered on Day 1 every three weeks for intravenous infusion. Abraham teaches another embodiment wherein 400 mg pembrolizumab or pembrolizumab variant is administered on Day 1 every six weeks and 800 mg Ab6 or Ab6 variant is administered on Day 1 every three weeks for intravenous infusion.
Denker teaches methods for treating cancer comprising administering to the individual a combination therapy of pembrolizumab and lenvatinib. Lenvatinib is administered orally at a daily dose of 24 mg, 20 mg or 14 mg, and pembrolizumab is administered at a dose of 200 mg every three weeks. Denker further teaches that lenvatinib can be administered orally once a day starting on Day 1 after completion of pembrolizumab, as 4 mg or 10 mg capsules.
It would have been obvious to one of ordinary skill in the art to modify the issued patent by obtain dosing protocols for pembrolizumab, Ab6, and lenvatinib from those available in the art. Given that Abraham teaches a dosing schedule for pembrolizumab and anti-LAG3 antibody Ab6, and Denker teaches dosing protocols for pembrolizumab and lenvatinib, one would have a reasonable expectation of success of combining these protocols because clinical results show that the double drug combinations (e.g., pembro + Ab6 or pembro + lenvatinib) work synergistically to treat various cancers, and this therapeutic benefit can be increased by combining all three drugs. As such, the instant claimed invention is an obvious modification of the claims of the issued patent in view of Denker and Abraham.
Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 36, and 39 of copending Application No. 18/485,688, in view of Denker et al. (WO 2016/141218; cited on IDS 9/5/2024) (“Denker”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a formulation comprising the identical anti-LAG3 and anti-PD-1 antibodies, Ab6 and pembrolizumab, respectively, as recited in the instant claims.
The instant claims differ from the copending claims in that they do not explicitly teach the Ab6 + pembrolizumab composition further comprises lenvatinib, or that the composition can be used for the treatment of cancer.
The teachings of Denker have been set forth above. Specifically, Denker teaches methods and compositions for treating cancer comprising administering to an individual a combination of an anti-PD-1 antibody and lenvatinib.
It would have been obvious to one of ordinary skill in the art to modify the composition of the copending claims by adding lenvatinib, which has been shown to boost the therapeutic potential of checkpoint inhibitor combination therapies, including anti-PD-1 antibodies as evidenced by Denker. As such, the instant claimed invention is an obvious modification of the copending claims in view of Denker.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 23-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 36, and 39 of copending Application No. 18/485,688, in view of Denker et al. (WO 2016/141218; cited on IDS 9/5/2024) (“Denker”) and Abraham et al. (WO 2020/096917; cited on IDS 7/19/2024) (“Abraham”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a formulation comprising the identical anti-LAG3 and anti-PD-1 antibodies, Ab6 and pembrolizumab, respectively, as recited in the instant claims.
The instant claims differ from the copending claims in that they do not teach a dosing protocol.
The teachings of Denker and Abraham and have been set forth above.
Specifically, Abraham teaches 200 mg pembrolizumab or pembrolizumab variant and 800 mg Ab6 or Ab6 variant are co-administered on Day 1 every three weeks for intravenous infusion. Abraham teaches another embodiment wherein 400 mg pembrolizumab or pembrolizumab variant is administered on Day 1 every six weeks and 800 mg Ab6 or Ab6 variant is administered on Day 1 every three weeks for intravenous infusion.
Denker teaches methods for treating cancer comprising administering to the individual a combination therapy of pembrolizumab and lenvatinib. Lenvatinib is administered orally at a daily dose of 24 mg, 20 mg or 14 mg, and pembrolizumab is administered at a dose of 200 mg every three weeks. Denker further teaches that lenvatinib can be administered orally once a day starting on Day 1 after completion of pembrolizumab, as 4 mg or 10 mg capsules.
It would have been obvious to one of ordinary skill in the art to modify the copending claims to obtain dosing protocols for pembrolizumab, Ab6, and lenvatinib from those available in the art. Given that Abraham teaches a dosing schedule for pembrolizumab and anti-LAG3 antibody Ab6, and Denker teaches dosing protocols for pembrolizumab and lenvatinib, one would have a reasonable expectation of success of combining these protocols because clinical results show that the double drug combinations (e.g., pembro + Ab6 or pembro + lenvatinib) work synergistically to treat various cancers, and this therapeutic benefit can be increased by combining all three drugs. As such, the instant claimed invention is an obvious modification of the claims of the copending claims in view of Denker and Abraham.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4 and 8-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-20 and 25-27 of copending Application No. 18/826,658, in view of Huang et al. (Oncotarget, 2015; 6:27359-27377) (“Huang”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a method for treating cancer by administering pembrolizumab + lenvatinib with the same dosing schedule (200 mg, Q3W) as recited in the instant claims.
The instant claims differ from the copending claims in that they do not explicitly teach the pembrolizumab + lenvatinib composition further comprises a LAG3 antagonist.
The teachings of Huang have been set forth above. Specifically, Huang teaches mice with ovarian cancer administered a single blockade therapy of an anti-PD1 or anti-LAG3 antibody did not have a significant benefit from treatment, however, combinatorial blockade with anti-LAG3 and anti-PD1 antibodies significantly delayed the growth of the ovarian tumors. In addition, Huang tested the antibody blockade in a subcutaneous OVA-expressing lymphoma EG7 tumor model. Treatment with dual anti-LAG3/PD1 antibodies resulted in tumor rejection in 100% of the mice.
It would have been obvious to one of ordinary skill in the art to modify the copending claims to include an anti-LAG3 antibody given that Huang teaches anti-LAG3 + anti-PD-1 antibody work in a synergistic manner to reduce tumor burden in various cancers. A skilled artisan would have a reasonable expectation of success in combining the methods because both combination treatments, anti-PD-1 + lenvatinib and anti-PD-1 + anti-LAG3, were effective in reducing tumor growth up to 100% when administered as dual blockade therapies, and it would be expected that administration with anti-PD-1 + anti-LAG3 + lenvatinib would work in a similar synergistic manner. As such, the instant claimed invention is an obvious modification of the copending claims in view of Huang.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-7, 12-19, and 23-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-20 and 25-27 of copending Application No. 18/826,658, in view of Abraham et al. (WO 2020/096917; cited on IDS 7/19/2024) (“Abraham”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a method for treating cancer by administering pembrolizumab + lenvatinib with the same dosing schedule (200 mg, Q3W) as recited in the instant claims.
The instant claims differ from the copending claims in that they do not explicitly teach the pembrolizumab + lenvatinib composition further comprises a LAG3 antagonist, and no amino acid sequences for the antibodies are disclosed.
The teachings of Abraham are set forth above.
Abraham teaches a combination of pembrolizumab + Ab6. Abraham provides the amino acid sequences for pembrolizumab and Ab6, including the 6 CDR regions, as recited in the instant claims. Abraham further teaches 200 mg pembrolizumab and 800 mg Ab6 are co-administered on Day 1 every three weeks for intravenous infusion or 400 mg pembrolizumab is administered on Day 1 every six weeks and 800 mg Ab6 is administered on Day 1 every three weeks for intravenous infusion.
It would have been obvious to one of ordinary skill in the art at the time of filing the instant invention to obtain the protein sequences for an anti-PD-1 antibody and an anti-LAG3 antibody, from those available in the prior art as evidenced by Abraham. One would have a reasonable expectation of success in modifying the protocols of the copending claims by adding the Ab6 anti-LAG3 antibody taught by Abraham to because Abraham teaches pembro + Ab6 work synergistically to treat cancer. As such, the instant claimed invention is an obvious modification of the copending claims in view of Abraham.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 17/274,531
One or more claims of the instant application are either anticipated and/or rendered obvious by the copending claims of the ‘531 application in view the cited references. However, the copending application has been legally abandoned for failure to respond to the last Office Action mailed March 17, 2025. Accordingly, provisional double statutory rejection(s) are not being raised.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644