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 .
Claim Status
The preliminary amendment filed August 6, 2024 have been received and entered.
Claim 70 has been amended.
Claims 1-17 and 25-68 have been canceled.
Claims 18-24 and 69-81 are pending and under consideration.
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 PCT/US2022/080312 filed 11/22/2022, which claims the benefit of U.S. Provisional Application Nos. 63/283,155, 63/283,158, and 63/283,152, all filed on 11/24/2021.
However, Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosures of the prior provisional applications fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a), first paragraph for one or more claims of this application.
Instant claims 23 and 76 recite amino acid sequences (SEQ ID NOs) for cyclic peptides 17-33. None of the provisional applications disclose these sequences.
The first occurrence of the amino acid sequences for instantly claimed naturally occurring q-defensin cyclic peptides 17-33, comprising SEQ ID NOs: 17-33, respectively is in the disclosure of the PCT/US2022/080312 application filed 11/22/2022.
Should Applicant disagree with the examiner’s factual determination as to the disclosure of the various claim limitations, Applicant may point out the particular places within the provisional applications which discloses the specific subject matter.
Accordingly claims 18-22, 24, 69-75, and 77-81 have an earliest effective filing date of 11/24/2021, corresponding to Provisional Application No. 63/283,155 which discloses the amino acid sequences (SEQ ID NOs) of cyclic peptides 1-16. Claims 23 and 76 have an earliest effective filing date of 11/22/2022, corresponding to PCT/US2022/080.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted 3/1/2025 and 11/11/2025 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 18-19 are objected to because of the following informalities:
Claim 18 – recites “immune checkpoint inhibitor (ICI)”, however, no other claims recite “ICI”. It is suggested that the parenthetical “(ICI)” be deleted from the claim, or alternatively, be added to all claims that recite an immune checkpoint inhibitor.
Claim 19 – recites “theta defensin”, however, the other instant claims recite “q-defensin”. It is suggested the claim be amended to recite “theta (q)-defensin” upon first use.
Appropriate correction is required.
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.
WRITTEN DESCRIPTION
Claims 18, 22, 24, 71, 75, and 77-81 are rejected under 35 U.S.C. 112(a), 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, 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 18 is drawn to a method for enhancing immune checkpoint inhibitor therapy, comprising administering an effective amount of a cyclic peptide in combination with an immune checkpoint inhibitor (ICI).Claim 71 is drawn to a kit comprising a cyclic peptide and an immune checkpoint inhibitor.
The claims encompass a large genus of structurally distinct cyclic peptides.
The specification provides no limiting definition for cyclic peptides. The specification only discloses that cyclic peptides can be naturally occurring (e.g., θ-defensins) or synthetic (e.g., analogs of naturally occurring cyclic peptides) [0009].
The specification further discloses naturally occurring cyclic peptides isolated from natural sources consisting of peptide 17 (SEQ ID NO. 17), peptide 18 (SEQ ID NO. 18), peptide 19 (SEQ ID NO. 19), peptide 20 (SEQ ID NO. 20), peptide 21 (SEQ ID NO. 21), peptide 22 (SEQ ID NO. 22), peptide 23 (SEQ ID NO. 23), peptide 24 (SEQ ID NO. 24), peptide 25 (SEQ ID NO. 25), peptide 26 (SEQ ID NO. 26), peptide 27 (SEQ ID NO. 27), peptide 28 (SEQ ID NO. 28), peptide 29 (SEQ ID NO. 29), peptide 30 (SEQ ID NO. 30), peptide 31 (SEQ ID NO. 31), peptide 32 (SEQ ID NO. 32), and peptide 33 (SEQ ID NO. 33) [0041 and Table 2].
The examples set forth in the specification test the effect of cyclic peptide analogs, peptide 1 (SEQ ID NO: 1), peptide 2 (SEQ ID NO: 2), peptide 3 (SEQ ID NO: 3), and naturally occurring peptide 17 (SEQ ID NO: 17) in combination with an anti-PD-1 antibody (RMP1-14).
The first example shows peptide 1 (SEQ ID NO: 1) in combination with anti-PD-1 was more effective than either therapeutic as a monotherapy for the treatment in a mouse model of melanoma, wherein complete tumor regression was observed [[0083-0085], Fig. 4-5]. A similar result was observed when mice were treated with natural cyclic peptide 17 (SEQ ID NO: 17) [[00102-00103], Fig. 13].
The second example shows peptide 1 (SEQ ID NO: 1), peptide 2 (SEQ ID NO: 2), and peptide 3 (SEQ ID NO: 3) administered in combination with anti-PD-1 in a mouse model of colon adenocarcinoma potentiated survival than either therapeutic as a monotherapy [[0086-0089], Fig 7-10].
Thite et al. (2026) teach cyclic peptides represent a structurally diverse class of biomolecules that can be categorized according to their source, the nature of the bonds forming the ring, and the number of amino acid residues involved. From a source perspective, they may be either naturally occurring, produced by microorganisms, plants, or marine organisms, or synthetically generated through chemical synthesis for tailored pharmacological applications. Based on the type of bond, cyclic peptides can be divided into homodetic, isopeptide, and depsipeptide classes. Classification by ring size further highlights the functional diversity of cyclic peptides. Cyclic dipeptides, or diketopiperazines, are the simplest members, typically rigid and resistant to proteolysis. Tripeptides, slightly larger and more conformationally flexible, have been reported to exhibit antioxidant and anti-inflammatory properties. Tetrapeptides, with reduced ring strain, display enhanced stability. In general, tetra- and pentapeptides are considered the threshold for reliable stabilization, as smaller rings such asdi- andtripeptides may suffer from ring strain, while larger macrocyclic structures gain conformational stability and functional versatility [Section 3.2].
Therefore, the properties of one cyclic peptide cannot be applied to other cyclic peptides. Thus, the properties of the claimed cyclic peptides encompassed by claim 18, are not predictive of the full genus of cyclic peptides.
Claims 22 and 75 limit the cyclic peptide to a naturally occurring q-defensin.
Regarding naturally occurring defensins in general, Conibear et al. (2014) teach ribosomally synthesized cyclic peptides have been discovered in bacteria, fungi, plants, and animals, and have a wide range of sizes, structures, and biological properties [1.1 Introduction].
Regarding natural q-defensins, Conibear et al. teach theta (q)-defensins are the only known class of cyclic peptides from mammals [1.1 Introduction]. The first cyclic mammalian peptide, rhesus θ‐defensin 1 (RTD‐1), is an 18‐residue peptide with potent antibacterial activity [Section 2.2]. Conibear et al. teach there are 11 different q-defensins comprising structurally different peptides [Section 3.1,Fig. 4].
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 cyclic peptides or natural q-defensins encompassing various structures, specificities and functions. Further, 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.
Given the claimed broadly class of cyclic peptides, 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. There is insufficient written description of the required kind of structure- identifying information about the corresponding makeup of the claimed cyclic peptides 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 24 and 77-81 are included in the rejection because they depend from or otherwise require all the limitations of the rejected claim and fail to resolve the issue.
ENABLEMENT
Claims 18-19, 21-23, 71-72, 74-79, and 81 are rejected under 35 U.S.C. 112(a), first paragraph, because the specification, while being enabling for improving immune checkpoint inhibitor therapy comprising coadministration of cyclic peptide 1 (SEQ ID NO: 1), cyclic peptide 2 (SEQ ID NO: 2), cyclic peptide 3 (SEQ ID NO: 3), or cyclic peptide 17 (SEQ ID NO: 17) with an anti-PD-1 antibody; does not reasonably provide enablement for improving immune checkpoint inhibitor therapy with any cyclic peptide or any immune checkpoint inhibitor as broadly claimed.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP § 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
Claim 18 is drawn to a method for enhancing immune checkpoint inhibitor therapy, comprising administering an effective amount of a cyclic peptide in combination with an immune checkpoint inhibitor (ICI).
Claim 71 is drawn to a kit comprising a cyclic peptide and an immune checkpoint inhibitor.
Claims 19 and 72 limit the cyclic peptide to an analog of a theta (q)-defensin.
Claims 21 and 74 recite the cyclic peptide analog is one of cyclic peptides 1-16 (SEQ ID NOs 1-16).
Claims 22 and 75 limit the cyclic peptide to a naturally occurring q-defensin.
Claims 23 and 76 recite the naturally occurring cyclic peptide is one of cyclic peptides 17-33 (SEQ ID NOs 17-33).
Claim 79 limits the immune checkpoint inhibitor to an anti-natural killer cell receptor 2B4 (2B4), anti-B- and T-lymphocyte attenuator (BTLA), anti-CD 160 antigen (CD 160), anti-cytotoxic T-lymphocyte protein 4 (CTLA-4), anti- lymphocyte activation gene 3 protein (LAG-3), anti-programmed cell death protein 1 (PD-1), anti-T-cell immunoglobulin mucin receptor 3 (TIM-3), and an anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) agents/inhibitor.
Claim 81 is drawn to a kit comprising a cyclic peptide and an immune checkpoint inhibitor.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
Thite et al. (2026) teach cyclic peptides represent a structurally diverse class of biomolecules that can be categorized according to their source, the nature of the bonds forming the ring, and the number of amino acid residues involved. From a source perspective, they may be either naturally occurring, produced by microorganisms, plants, or marine organisms, or synthetically generated through chemical synthesis for tailored pharmacological applications. Based on the type of bond, cyclic peptides can be divided into homodetic, isopeptide, and depsipeptide classes. Classification by ring size further highlights the functional diversity of cyclic peptides. Cyclic dipeptides, or diketopiperazines, are the simplest members, typically rigid and resistant to proteolysis. Tripeptides, slightly larger and more conformationally flexible, have been reported to exhibit antioxidant and anti-inflammatory properties. Tetrapeptides, with reduced ring strain, display enhanced stability. In general, tetra- and pentapeptides are considered the threshold for reliable stabilization, as smaller rings such asdi- andtripeptides may suffer from ring strain, while larger macrocyclic structures gain conformational stability and functional versatility [Section 3.2].
Regarding naturally occurring defensins in general, Conibear et al. teach ribosomally synthesized cyclic peptides have been discovered in bacteria, fungi, plants, and animals, and have a wide range of sizes, structures, and biological properties [1.1 Introduction].
Regarding natural q-defensins, Conibear et al. teach theta (q)-defensins are the only known class of cyclic peptides from mammals [1.1 Introduction]. The first cyclic mammalian peptide, rhesus θ‐defensin 1 (RTD‐1), is an 18‐residue peptide with potent antibacterial activity [Section 2.2]. Conibear et al. teach there are 11 different q-defensins comprising structurally different peptides [Section 3.1,Fig. 4].
Regarding q-defensin analogs, Conibear et al. (2014) teach there are many synthetic analogs with varying numbers and arrangements of disulfide bonds. Conibear et al. teach analogues with three, two, or one central disulfide bond are structured and stable, while those lacking disulfide bonds or a cyclic backbone are unstructured and rapidly degraded in serum [Section 5.2].
Regarding immune checkpoint inhibitors, Linhares et al. (2018) teach not all immune checkpoints are equal [Title]. PD-1, CTLA-4, BTLA, LAG-3, and TIM-3 are considered the major inhibitory immune checkpoints expressed on T cells [Abstract]. BTLA, LAG-3, TIM-3, and CTLA-4 deviate from the classical inhibitory receptors and differ considerably from PD-1, which can be regarded as the prototypic T cell-expressed immune checkpoint that induces inhibitory intracellular signaling upon engagement with its non-signaling ligands that are preferentially expressed on antigen-presenting cells (APC) and tumor cells. [Introduction].
Given the lack of predictability of immune checkpoint inhibitors combined with the varying structure of cyclic peptides, one of ordinary skill in the art would have to engage in undue experimentation to identify which cyclic peptide would improve a specific immune checkpoint inhibitor therapy.
(3) The relative skill of those in the art:
The relative skill in the art is high for those with an M.D. or Ph.D.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples:
The specification discloses that the cyclic peptides are naturally occurring RTD-1, or analogs thereof. Analogs of cyclic peptides include peptide 1 (SEQ ID NO. 1), peptide 2 (SEQ ID NO. 2), peptide 3 (SEQ ID NO. 3), peptide 4 (SEQ ID NO. 4), peptide 5 (SEQ ID NO. 5), peptide 6 (SEQ ID NO. 6), peptide 7 (SEQ ID NO. 7), peptide 8 (SEQ ID NO. 8), peptide 9 (SEQ ID NO. 9), peptide 10 (SEQ ID NO. 10), peptide 11 (SEQ ID NO. 11), peptide 12 (SEQ ID NO. 12), peptide 13 (SEQ ID NO. 13), peptide 14 (SEQ ID NO. 14), peptide 15 (SEQ ID NO. 15), and peptide 16 (SEQ ID NO. 16) [0040 and Table 1].
The specification further discloses naturally occurring cyclic peptides isolated from natural sources consisting of peptide 17 (SEQ ID NO. 17), peptide 18 (SEQ ID NO. 18), peptide 19 (SEQ ID NO. 19), peptide 20 (SEQ ID NO. 20), peptide 21 (SEQ ID NO. 21), peptide 22 (SEQ ID NO. 22), peptide 23 (SEQ ID NO. 23), peptide 24 (SEQ ID NO. 24), peptide 25 (SEQ ID NO. 25), peptide 26 (SEQ ID NO. 26), peptide 27 (SEQ ID NO. 27), peptide 28 (SEQ ID NO. 28), peptide 29 (SEQ ID NO. 29), peptide 30 (SEQ ID NO. 30), peptide 31 (SEQ ID NO. 31), peptide 32 (SEQ ID NO. 32), and peptide 33 (SEQ ID NO. 33) [0041 and Table 2].
The examples set forth in the specification test the effect of cyclic peptide analogs, peptide 1 (SEQ ID NO: 1), peptide 2 (SEQ ID NO: 2), peptide 3 (SEQ ID NO: 3), and naturally occurring peptide 17 (SEQ ID NO: 17) in combination with an anti-PD-1 antibody (RMP1-14).
The first example shows peptide 1 (SEQ ID NO: 1) in combination with anti-PD-1 was more effective than either therapeutic as a monotherapy for the treatment in a mouse model of melanoma, wherein complete tumor regression was observed [[0083-0085], Fig. 4-5]. A similar result was observed when mice were treated with natural cyclic peptide 17 (SEQ ID NO: 17) [[00102-00103], Fig. 13].
The second example shows peptide 1 (SEQ ID NO: 1), peptide 2 (SEQ ID NO: 2), and peptide 3 (SEQ ID NO: 3) administered in combination with anti-PD-1 in a mouse model of colon adenocarcinoma potentiated survival than either therapeutic as a monotherapy [[0086-0089], Fig 7-10].
Thus, it would be difficult for one of ordinary skill in the art to envisage any cyclic peptide could improve the therapeutic benefit of all immune checkpoint inhibitors as recited in the instant claims.
Thus, based on the unpredictability of the art and the breadth of the claims, the instant
specification must provide a sufficient and enabling disclosure commensurate in scope with the instant
claims. It would require enormous amount of trial and error in order to identify a cyclic peptide for the use combination treatment with an immune checkpoint inhibitor that improves the benefit of said immune checkpoint inhibitor than either therapeutic alone. This is not in commensurate in scope with the instant claims, which encompass any cyclic peptide and any immune checkpoint inhibitor. Thus, it would require undue experimentation to practice the full scope of the claimed method. Specifically, one cannot envisage all cyclic peptides, natural and synthetic, to have the same properties as recited in the instant claims. However, the explicit examples provided in the instant specification fall within a genus that is not fully enabled.
Claims 77-78 are included in the rejection because they depend from and require all the limitations of a rejected claim.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 18, 22-23, and 75-76 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements, which are recited in a high level of generality, provide conventional generic methods of treatment comprising administration of the instantly claimed combination therapy that do not add meaningful limits to practicing the law of nature.
The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). See MPEP 2106. The first step of the analysis asks whether the claimed invention is directed to a statutory category of invention.
Claims 18 and 71 are drawn to a method of enhancing immune checkpoint inhibitor therapy, comprising administering an effective amount of any cyclic peptide in combination with any immune checkpoint inhibitor.
Claims 22 and 75 recite the instantly claimed cyclic peptides are naturally occurring theta (q)-defensins.
Claims 23 and 76 recite the naturally occurring q-defensins comprise peptide 17 (SEQ ID NO. 17), peptide 18 (SEQ ID NO. 18), peptide 19 (SEQ ID NO. 19), peptide 20 (SEQ ID NO. 20), peptide 21 (SEQ ID NO. 21), peptide 22 (SEQ ID NO. 22), peptide 23 (SEQ ID NO. 23), peptide 24 (SEQ ID NO. 24), peptide 25 (SEQ ID NO. 25), peptide 26 (SEQ ID NO. 26), peptide 27 (SEQ ID NO. 27), peptide 28 (SEQ ID NO. 28), peptide 29 (SEQ ID NO. 29), peptide 30 (SEQ ID NO. 30), peptide 31 (SEQ ID NO. 31), peptide 32 (SEQ ID NO. 32), and peptide 33 (SEQ ID NO. 33).
The claims are directed to a method, which is a statutory category of invention and therefore meets the requirements of the first step of the analysis.
Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception (see MPEP 2106). Based upon an analysis with respect to the claims as a whole, the instant claims are determined to be directed to a law of nature.
Third, a claim that focuses on the use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. See Mayo 101 USPQ2d at 1966. Adding steps to a natural biological process that only recite well-understood, routine, conventional activity previously engaged in by researchers in the field would not be sufficient. See id. At 1966, 1970. The instant claims merely combine the instantly claimed cyclic peptide and immune checkpoint inhibitor in a method of improving immune checkpoint inhibitor therapy, however, no treatment dosing or other method steps are recited.
Therefore, it can be said that the recited methods of treatment (combing two therapeutics) are determined as a well-understood, routine, and conventional activity: see Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017). Therefore, the additional features of the claims (i.e., comingling the cyclic peptide and immune checkpoint inhibitor in the same composition, or a kit comprising said cyclic peptide and immune checkpoint inhibitor) do not ensure that the claims amount to significantly more than the natural principle itself.
Regarding naturally occurring defensins in general, Conibear et al. (2014) teach ribosomally synthesized cyclic peptides have been discovered in bacteria, fungi, plants, and animals, and have a wide range of sizes, structures, and biological properties [1.1 Introduction].
Regarding natural q-defensins specifically, Conibear et al. teach theta (q)-defensins are the only known class of cyclic peptides from mammals [1.1 Introduction]. The first cyclic mammalian peptide, rhesus θ‐defensin 1 (RTD‐1), is an 18‐residue peptide with potent antibacterial activity [Section 2.2]. Conibear et al. teach there are 11 different q-defensins comprising structurally different peptides [Section 3.1,Fig. 4].
Regarding immune checkpoint inhibitors, Chun et al. (2022) teach the most generally used immunotherapy is the control of immune checkpoints including the cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), programmed cell death receptor 1 (PD-1), or programmed cell death ligand-1 (PD-L1). However, in spite of the clinical effectiveness of immune checkpoint inhibitors, the overall response rate still remains low. Chun et al. teach that natural compounds present in medicinal or dietary plants exert anti-tumor activities and synergistic anti-cancer effects of diverse phytochemicals with anti-PD-1/PD-L1 or anti-CTLA-4 monoclonal antibody drugs have been reported [Abstract]. Chun et al. teach that phytochemicals are anticipated to overcome the limitation of PD-1/PD-L1 or CTLA-4 antibody drugs due to their multi-functional benefits. These include direct blockade of interaction between proteins involved in immune checkpoint signal transduction, regulation of their expression, and combined effects with a given immune checkpoint inhibitor [Section 1, Introduction].
Chun et al. teach several phytochemicals that act as immune checkpoint inhibitors. For example, Banxia xiexin decoction, a classical formula used for Chinese herbal medicine, inhibits the expression PD-L1 through downregulation of HIF-1, EGFR and TLR4 expression, thereby inhibiting the proliferation of gastric cancer cells [Section 5]. Other phytochemicals in plant-based diet and herbs or spice exert anti-tumor effects by modulating immune checkpoint protein networking including curcumol, resveratrol, berberine, apigenin, ginsenosides, silibinin, EGCG, hesperidin, among others [Table 1]. Some phytochemicals have also been shown to possess anti-tumoral immune modulatory activities in animal tumor models and clinical settings including curcumin, theracurcumin, curcumol, resveratrol, luteolin, shikonin, among others [Table 2].Therefore, both cyclic peptides and immune checkpoint inhibitors broadly include their naturally occurring forms. Furthermore, the peptides comprising the amino acid sequences of SEQ ID NOs: 17-33 further define a naturally occurring cyclic peptide that falls within the scope of claims 22-23 and 75-76 that was isolated from a natural source. This is evidence that cyclic peptides, including peptides 17-33, appear in nature and therefore the claimed invention appears to be a product that is not markedly different in structure from naturally occurring products. The claims inform a relevant audience about certain laws of nature; and additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community, and those steps, when viewed as a whole, add nothing significant beyond the sum of the parts taken separately. Even though the laws of nature at issue are narrow laws that may have limited applications, the claim does not amount to significantly more than the natural law itself.
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 18-19, 21-24, 71-72, and 74-81 are rejected under 35 U.S.C. 103 as being unpatentable over Tran et al. (WO 2020/076925; cited IDS 3/21/2025) (“Tran”) in view of Zahnow et al. (WO 2017/035453; cited IDS 3/21/2025) (“Zahnow”).
Tran teaches compositions for formulations of q-defensin and/or a q-defensin analog [Abstract]. q-defensins are expressed in Old World monkeys (e.g., macaques and baboons), and are the only known cyclic proteins in animals, with the RTD-1 isoform (SEQ ID NO: 1) being the most abundant in macaques [0007]. Tran teaches q-defensins have anti-inflammatory properties both in vitro and in vivo. For example, q-defensin RTD-1 is a potent inhibitor of cytokine secretion by human peripheral blood leukocytes stimulated with diverse Toll-like receptor (TLR) agonists [010].
Tran teaches a method of treating an individual with a chronic inflammatory condition, such as inflammation associated with cancer, by administering a pharmaceutical composition comprising a q-defensin or q-defensin analog [0017, 0019] (instant claim 18 partial).
Suitable q-defensins include native q-defensins found in mammals expressing these peptides, and can also include one or more q-defensins derived from untranslated genes present in some primate species (e.g. Homo sapiens). One or more q-defensins can correspond to those found in macaques; RTD-1 (SEQ ID NO: 1), RTD-2 (SEQ ID NO: 2), RTD-3 (SEQ ID NO: 3), RTD-4 (SEQ ID NO: 4), RTD-5 (SEQ ID NO: 5), and/or RTD-6 (SEQ ID NO: 6) [0036]. Others are found in baboons, e.g., BTD-3 (SEQ ID NO: 9) (instant claims 22-23, 75-76).
Tran teaches q-defensin analogs are share a high sequence identity with a native q-defensin, incorporating one, two, three, or more disulfide bonds within the peptide. The q-defensin analogs are 10 to 20 or more amino acids in length, and can incorporate non-naturally occurring amino acids. Tran teaches RTD-1 is the base for q-defensin analog RTD-1-28 (SEQ ID NO: 18) [0037] (instant claims 19, 21, 72, 74).
Tran teaches that the drug composition can include, in addition to one or more q-defensins and/or q-defensin analogs, additional therapeutic compounds, such as antibodies directed at proinflammatory cytokines [0050] (instant claim 18 partial).
The amino acid sequences for the naturally occurring q-defensins RTD-1 (SEQ ID NO: 1) and baboon BTD-3 (SEQ ID NO: 9) are 100% identical to the amino acid sequences of peptide 17 (SEQ ID NO: 17) and peptide 25 (SEQ ID NO: 25), respectively, as recited in the instant claims.
The amino acid sequence for q-defensin analog RTD-1-28 (SEQ ID NO: 18) is 100% identical to the amino acid sequence of peptide 15 (SEQ ID NO: 15) recited in the instant claims.
Tran does not teach administering a combination of a cyclic peptide and an immune checkpoint inhibitor as method to enhance the immune checkpoint inhibitor therapy.
Zahnow teaches methods of treating solid tumors with a combination therapy including a checkpoint inhibitor (instant claim . The checkpoint inhibitor is a monoclonal antibody that inhibits one or more checkpoint protein such as CTLA-4, PDL1, PDL2, LAG3, and VISTA among others [pg. 13, lines 29-34] (instant claims 79).
Specifically, Zahnow teaches anti-PD-1 antibodies that can act as agonists of PD-1, thereby modulating immune responses regulated by PD-1 [pg. 15, lines 23-24] (instant claim 24).
As an example, Zahnow teaches compositions comprising a demethylating agent and an HDAC inhibitor in combination with a checkpoint inhibitor that are combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either was used alone [pg. 18, lines 17-19] (instant claims 18 partial, 77). The HDAC inhibitor can be formulated together [pg. 23, lines 13-14] (instant claim 78).
Additionally, Zahnow teaches kits comprising the HDAC inhibitor and a checkpoint inhibitor and instructions for approved uses [pg. 31, lines 15-16, 33] (instant claims 71, 81).
The teachings of Tran differ from the present invention in that although natural q-defensins and q-defensin analogs are effective in reducing inflammatory effects associated with cancer and can be combined with other therapeutic compounds, combination with an immune checkpoint inhibitor is not. Given that Zahnow teaches a HDAC inhibitor in combination with anti-PD-1 antibodies effectively eliminates solid tumors in a synergistic fashion, one of ordinary skill in the art would have a reasonable expectation of success that when combining a q-defensin with an immune checkpoint inhibitor, such as an anti-PD-1 antibody, results in a more effective treatment than either one alone.
Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Allowable Subject Matter
Claims 20, 69-70, and 73 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The claims are drawn q-defensin analog peptides: peptide 1 (SEQ ID NO: 1), peptide 2 (SEQ ID NO: 2), and peptide 3 (SEQ ID NO: 3). There is no prior art that teaches or suggests q-defensin analog peptides with the specific amino acid sequences as recited in the instant claims.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
