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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 9, 2026 has been entered.
Claim Status
Claims 10, 20-22, and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 4, 6, 12, 16-19, 23, and new claims 25-33 are under consideration in this office action.
Withdrawn Rejections
Any objection or rejection of record pertaining to cancelled claims 7, 9, and 15 is rendered moot by applicant’s cancellation of said claims.
The rejection of claims 4, 6, 12, 16-19, and 23 under 35 U.S.C. 102(a)(2) as being anticipated by US 20210030703 (“Kroemer”) is withdrawn in view of applicant’s amendment of claim 4 to include the limitation wherein the oxidative phosphorylation is increased compared to a subject to which the PD-1 signaling inhibitor is not administered.
Claim Objections
Claims 6, 12, 16-17, and 31 are objected to because of the following informalities:
In claim 12, there is an unnecessary “of” in line 4.
Claims 16 and 31 incorrectly recite a mass ratio for the PD-1 signaling inhibitor and “the pharmaceutical composition”. Claim should be amended to recite a mass ratio of PD-1 signaling inhibitor to “the polyamine”.
Claims 6 and 17 are directed to the same method of increasing oxidative phosphorylation by administering a PD-1 signaling inhibitor and a polyamine selected from the group consisting of spermine, isolated spermidine, putrescine, salts thereof and solvates thereof. Applicant is advised that should claim 6 be found allowable, claim 17 will be objected to under 37 CFR1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP 608.01(m). Appropriate correction is required.
Modified Rejections Necessitated by Amendment
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.
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 4, 6, 12, 16-19, and new claims 25-33 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.
“[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.
Claims 4, 6, 12, 16-19, and new claims 25-33 are directed to a method comprising administering a PD-1 signaling inhibitor that comprises and antibody. This genus of antibodies encompasses an unknown number of possible antibodies that can inhibit PD-1 signaling. As such, the antibodies are not limited to those that inhibit PD-1 or any other specific target downstream or upstream of PD-1.
Antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the 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 complementarity determining regions (CDRs) that 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 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 (see Almagro et al, Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1; PTO-892 from 9/8/2025).
There is no way to a priori look at an antigen sequence (e.g., PD-1 or PD-L1) and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (PTO-892 from 9/8/2025), who demonstrates that a single amino acid change in the heavy chain of an antibody that binds p-azophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (see abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg 11).
The specification does not provide adequate written description for the entire claimed genus of PD-1 signaling inhibitor, because one skilled in the art would be unable to immediately envision, recognize, or distinguish most of the members comprised within the genus claimed.
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.
In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of PD-1 pathway inhibitors, especially in view of the unpredictability of such an endeavor. The prior art, as evidenced by Edwards et al., 2003 (PTO-892 from 9/8/2025), teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do 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”).
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of two broad genera that encompass a diverse and huge number of possible antibodies and other agents that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
For claims drawn 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), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011). An antibody described only by functional characteristic, such as antibody that binds IL-1b or IL-6, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient 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).
In these method claims, with the exception of antibodies of specifically disclosed targets and actions (e.g., wherein the PD-1 signaling inhibitor is an anti-PD-1 antibody), the skilled artisan cannot envision the structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. 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).
Therefore, claims 4, 6, 12, 16-19, and new claims 25-33 do not meet the written description 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)(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.
Claims 12 and new claims 26-32 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 20210030703, filed March 11, 2019 (“Kroemer”; PTO-892 from 3/18/2026).
Independent claims 12 and 29 are drawn to a method of treating cancer and a method of enhancing the therapeutic effect of a PD-1 signaling inhibitor, respectively, by administering a polyamine and PD-1 signaling inhibitor.
Regarding claims 12 and 26-28, Kromer teaches methods comprising administering caloric restriction mimetics and an immunotherapy targeting the immune checkpoint molecule PD-1 for the treatment of cancer (abstract); the caloric restriction mimetic can be spermidine [0008] and the PD-1 inhibitor is an anti-PD-1 antibody [0092], which reads on the methods of instant claims 12 and new claim 27. Because the only active step recited in claim 12 is administration and because Kromer teaches this step, Kromer teaches the increase in oxidative phosphorylation in T cells, as required by claim 12. The composition of Kromer is simultaneously administered with at least at least one immune-checkpoint inhibitor [0123], which reads on instant claim 12. The caloric restriction mimetic can be spermidine [0008], which reads on new claim 27.
Kromer teaches that the cancer may be colon cancer [0017], which reads on new claim 26.
Kromer teaches that the antibody can be administered at a dose about 0.02-100 mg/kg and the caloric restriction mimetic can be administered at 0.1-100 mg/kg [0158], which reads on new claim 28. The calculated antibody to drug ratio of Kromer is 1:1 to 1:0.2, which overlaps with the mass ratio of the PD-1 signaling inhibitor to polyamine pharmaceutical composition of 1:2 to 1:0.1 of claim 28.
With respect to new claims 29-33, Kromer teaches a method of treating cancer, where administration of the combination of a caloric restriction mimetic and immune checkpoint inhibitor enhances therapeutic efficacy relative to the administration of the immune checkpoint inhibitor alone [0164], which reads on the method of enhancing a therapeutic effect of a PD-1 signaling inhibitor of claim 29. The composition of Kromer is simultaneously administered with at least at least one immune-checkpoint inhibitor [0123], which reads on claim 29. The PD-1 inhibitor is an anti-PD-1 antibody [0092], as in claim 29. The caloric restriction mimetic can be spermidine [0008], which reads on new claim 30.
Kromer teaches that the antibody can be administered at a dose about 0.02-100 mg/kg and the caloric restriction mimetic can be administered at 0.1-100 mg/kg [0158], which reads on new claims 32-33. The calculated antibody to drug ratio of Kromer is 1:1 to 1:0.2, which overlaps with the mass ratio of the PD-1 signaling inhibitor to polyamine pharmaceutical composition of 1:2 to 1:0.1 of new claims 31-32.
New Rejection Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 4, 6, 12, 16-19, 23, and new claims 25-33 are rejected under 35 U.S.C. 103 as being unpatentable over US 20210030703, filed March 11, 2019 (“Kroemer”; PTO-892 from 3/18/2026) in view of Jing et al, published April 9, 2018 (instant PTO-892).
Claim 4, 6, 16-19, 23 and new claim 25 are directed to a method of increasing oxidative phosphorylation in T cells by administering a polyamine and an antibody inhibitor of PD-1 signaling, wherein oxidative phosphorylation is increased compared to a subject to which the PD-1 signaling inhibitor is not administered.
Kromer teaches methods comprising administering caloric restriction mimetics and an immunotherapy targeting the immune checkpoint molecule PD-1 for the treatment of cancer (abstract); the caloric restriction mimetic can be spermidine [0008] and the PD-1 inhibitor is an anti-PD-L1 antibody ([0004], [00850]), [0092], as in instant claims 4, 6, 17-18, and 23.
The composition of Kromer is simultaneously administered with at least at least one immune-checkpoint inhibitor [0123], which reads on instant claim 19.
Kromer teaches that the antibody can be administered at a dose about 0.02-100 mg/kg and the caloric restriction mimetic can be administered at 0.1-100 mg/kg [0158], with a calculated antibody to drug ratio of 1:1 to 1:0.2, which overlaps with the mass ratio of the PD-1 signaling inhibitor to polyamine pharmaceutical composition of 1:2 to 1:0.1 of new claim 25.
Kromer does not expressly teach that oxidative phosphorylation is increased in T-cells in a subject administered the polyamine and PD-1 signaling inhibitor antibody compared to a subject not administered the PD-1 signaling antibody.
Jing et al teaches that the polyamine spermidine increases oxygen consumption rate (OCR) and oxidative phosphorylation in mouse neuroblastoma cells (abstract; pg 80, section 3.4). Further, spermidine increases autophagy of neuroblastoma cells (pg 80, section 3.5). Jing et al also teaches that spermidine can induce autophagy of human immune cells (pg 78, column 1, para 1).
Given that Kromer teaches a method of administering polyamine with an immune checkpoint inhibitor, and further given that Jing teaches that spermidine increases oxidative phosphorylation and autophagy in neuroblastoma cells and that spermidine increases autophagy of immune cells, one of ordinary skill in the art would employ spermidine in T cells with the reasonable expectation that spermidine would exhibit its known property of increasing oxidative phosphorylation, when administered alone or in combination with an anti-PD-1 antibody. Such would amount to more than the predictable use of a known product according to its establish function to obtain its expected biological effect.
Response to Arguments
Applicant's arguments filed June 9, 2026 have been fully considered.
With respect to the rejection under 35 U.S.C. 112(a) for reciting new matter limitation “isolated spermidine”, applicant’s arguments (pg 5) are persuasive and the rejection is withdrawn. Regarding the rejection of under 35 U.S.C. 112(a) as failing to meet the written description requirement for “PD-1 signaling inhibitor”, applicant asserts that PD-1 signaling antibodies are known in the art (Remarks, pg 5). This argument is not sufficient to overcome this part of the rejection because, when the claims are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification, the PD-1 signaling inhibitor that is an antibody is drawn to any of a number of different protein targets both upstream and downstream of PD-1 signaling. This rejection can be overcome by limiting the inhibitor to an anti-PD-1 antibody, which is sufficiently described by the existing art.
Regarding the rejection of claim 12 and 29 under 35 U.S.C. 102(a)(2) as being anticipated by Kroemer, applicant argues that Kroemer states that CRM therapy does not have an effect on tumor sensibility towards ICI immunotherapy. However, because the only active method step recited in claims 12 and 29 are administering to a subject a polyamine and a PD-1 signaling inhibitor antibody and because Kroemer teaches these steps, the reference inherently anticipates the method of treating cancer and the method of enhancing a therapeutic effect of a PD-1 signaling inhibitor. The rejections are maintained.
Conclusion
No claim is allowed.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
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