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 .
Applicant’s amendment, filed on 4/21/2026, is acknowledged.
Claims 1-26 are cancelled.
Claims 27-46 are currently pending.
Claims 1 and 46 are independent claims.
Election/Restrictions
Applicants’ election without traverse of Group I, claims 27-45, directed to a method of treating a cancer comprising administration of an αvβ3 and/or αvβ5 integrin targeting agent and at least one immunotherapeutic agent and/or at least one chemotherapeutic agent; and the Species of: i) NSCLC as the cancer; ii) SEQ ID NO: 9 as the integrin targeting agent, iii) an anti-PD1 antibody as the immunotherapeutic, and iv) cisplatin chemotherapeutic, filed on 4/21/2026, is acknowledged.
After reconsideration, the search and examination has been extended to encompass all species of the invention.
Claim 46 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention.
Claims 27-45 are under examination being drawn to a method of treating a cancer comprising administration of an αvβ3 and/or αvβ5 integrin targeting agent and at least one immunotherapeutic agent and/or at least one chemotherapeutic agent.
Priority
Applicant’s claim for the benefit of a prior-filed GB Application No. 2103122.4, filed on March 5, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/23/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner in its entirety.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency 1 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency 2 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Amino acid sequences are disclosed on:
pg. 13, line 26;
pg. 29, lines 27 and 28; without a corresponding sequence identifier.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The use of the term TruStain FcX™ (pg. 31, line 10) which is a trade name or mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 27-45 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claims 27-30 and 40-45 encompass methods of treating a cancer comprising administration of a broad genus of agents with no recited structure and the function of “αvβ3 and/or αvβ5 integrin targeting agent”.
Claims 31, 38, and 39 encompass methods of treating a cancer comprising administration of small molecules, peptides, peptidomimetics, proteins, and antibodies with no recited structure and the function of “αvβ3 and/or αvβ5 integrin targeting agent”.
Claim 32 encompasses methods of treating a cancer comprising administration of a broad genus of peptides comprising “an RGD motif”, as well as peptidomimetics thereof (which encompasses non-peptide structures as well) with little to no recited structure and the function of “αvβ3 and/or αvβ5 integrin targeting agent”.
Claim 33 encompasses methods of treating a cancer comprising administration of a broad genus of peptides comprising “an RGD motif”, as well as one of the amino acid residues recited in claim 33 and peptidomimetics thereof with little to no recited structure and the function of “αvβ3 and/or αvβ5 integrin targeting agent”.
Claim 34 encompasses methods of treating a cancer comprising administration of a broad genus of peptides comprising cilengitide or one of the motif sequences recited in the claim and derivatives, analogs, or peptidomimetics thereof with a partial structure at best and the function of “αvβ3 and/or αvβ5 integrin targeting agent”.
Claim 35 encompasses methods of treating a cancer comprising administration of a broad genus of peptides comprising SEQ ID NO: 5 or 28, and derivatives, analogs, or peptidomimetics thereof with a partial structure at best and the function of “αvβ3 and/or αvβ5 integrin targeting agent”.
Claims 36 and 37 encompass methods of treating a cancer comprising administration of a broad genera of prodrug peptides with no recited structure (claim 36), or at least one of the modifications recited in claim 37, and peptidomimetics thereof with a partial structure at best and the function of “αvβ3 and/or αvβ5 integrin targeting agent”.
Therefore, as they are currently written, claims 27-45 encompass broad genera of agents with a partial structure at best and the function of “αvβ3 and/or αvβ5 integrin targeting agent”, as well as methods of treating cancer comprising administration of the broad genus of agents in combination with at least on immunotherapeutic or at least one chemotherapeutic.
However, the specification fails to provide adequate written description support for a genus of antibody heavy chain constant regions with no recited structure having the desired functional properties required to practice the claimed functions of “αvβ3 and/or αvβ5 integrin targeting agent” or “treating cancer”.
The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
A "sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.
"A sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
The specification discloses use of specific engineered cyclic hexapeptides that bind to specific integrins, such as αvβ3 integrin, αvβ5 integrin, or both (Examples). Different examples of such cyclic peptides are disclosed (pg. 14, lines 2-14), however the integrins that the peptides bind to are not disclosed.
One cyclic peptide and a specific prodrug version of the peptide, 29 and 29P, are disclosed (SEQ ID NO: 28 and 9, respectively; Examples). The prodrug cyclic peptide 29P was found to modify the growth patterns of NSCLC to increase angiogenesis and vascular perfusion of tumors (Example 2, Fig. 2), which enhances the effect of co-administered therapeutics such as checkpoint inhibitors or chemotherapy such as cisplatin (Example 3, Fig. 3).
With respect to representative number of species, see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 Il(A)(3)(a))(ii):
A representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
In the instant case, the claims encompass broad genera of agents with little to no recited structure, including peptidomimetics, derivatives, and/or analogs of recited peptide sequences, which includes millions of different candidates with the recited structure of “αvβ3 and/or αvβ5 integrin targeting agent”. Furthermore, only one example of a structure with this function has been described that functions in a method of treating cancer, which is the 29P prodrug to be used in combination with checkpoint inhibitors and/or chemotherapy, which is the modified cyclic peptide c(*vR(Hoc)2GD(OMe)A*A).
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed methods of treating cancer comprising administration of integrin binding agents to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the broadly claimed class of binding agents, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed class of antigen binding molecules that bind to a ligand, 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), MPEP 2163.
The specification does not describe any methods of generating different agent structures with the function of “αvβ3 and/or αvβ5 integrin targeting agent”, or how to distinguish structures with this function from those without. The only guidance the instant specification provides is to list specific peptide structures with this function. Additionally, the specification does not disclose any methods to determine which of these structures would function in methods of treating cancer, only disclosing one structure (29P) with this function.
Additionally, the current state of the art teaches that there is unpredictability in determining which agent structures have the function of “αvβ3 and/or αvβ5 integrin targeting agent”, and which of these structures can function in methods of treating cancer.
For example, Ludwig et al. (Cancers (Basel). 2021 Apr 4;13(7):1711. doi: 10.3390/cancers13071711) teaches that RGD-based integrin ligands have been designed for use in biomedical applications (Section 4). Specifically regarding synthetic ligands comprising the RGD motif that bind to integrin αvβ3 or αvβ5, Ludwig et al. teaches that the RGD motif can be modified to generate ligand structures that bind to different integrins (Fig. 7):
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Ludwig et al. teaches that while some structures bind both αvβ3 and αvβ5 integrins selectively, such as compounds 1 and 6, other structures only bind αvβ3 (compound 5) or αvβ5 (compound 7), and some structures do not bind αvβ3 or αvβ5 (compounds 8-17). Additionally, Ludwig et al. teaches that specific structures can be modified to bind to different integrins. For example, Ludwig et al. teaches (pg. 18-20): “…MK-0429 is curious, as it has initially been described to target only αvβ3, but later low nanomolar affinities with IC50 values of 1.6, 2.8, 0.1, 0.7, 0.5, and 12.2 nM for αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, and α5β1, respectively, marking MK-0429 as an αv pan-integrin antagonist…two pure αvβ3 antagonists, TDI-3761 (ligand 3, Figure 7) and TDI-4161 (ligand 4, Figure 7) were synthesized through modifying MK-0429…” Ludwig et al. teaches that even minor changes to a structure can alter its integrin binding function, leading to unpredictability in predicting which structures would have the function of “αvβ3 and/or αvβ5 integrin targeting agent”
Additionally, Weinmüller et al. (Angew. Chem. Int. Ed.2017, 56, 16405. doi: 10.1002/anie.201709709) teaches an approach to identify different peptide structure that have the ability to bind to integrins (Abstract). Weinmüller et al. teaches that this approach involves screening very large peptide libraries for individual structures that bind to different integrins, followed by selection of these structures (Abstract): “[t]he key steps of the method are 1) initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala5); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD-recognizing integrin subtypes…” Weinmüller et al. identified and selected different peptide structures from the screen that bound integrin (Table 2):
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Weinmüller et al. that different peptide structures have widely varying integrin binding characteristics. For example, rG*DA*AA (a 6-residue peptide of the sequence (D)-Arg, Gly, N-methylated Asp, Ala, N-methylated Ala, Ala) has very low binding to integrin αvβ3, while *rGDA*AA (a 6-residue peptide of the sequence N-methylated (D)-Arg, Gly, Asp, Ala, N-methylated Ala, Ala) binds strongly to αvβ3 despite having the same six amino acid residues, albeit modified slightly differently.
Additionally, Weinmüller et al. teaches that different peptide compounds have different properties such as cell permeability (pg. 16407, Fig. 2): “[c]ompounds 5, 12, 17, 23, 29, and 30 were evaluated for their intestinal permeability in the Caco-2 model. All peptides had significantly reduced permeability… 29 and its prodrug 29P are presented in Figure 2d. The results show that the lipophilic, charge masked prodrug has a significantly increased permeability rate compared to the respective unmasked peptide…”
Additionally, regarding the claimed methods of treating cancer, the prior art teaches that there is unpredictability in using such integrin targeting in methods of treating cancer. For example, Stupp et al. (Lancet Oncol. 2014 Sep;15(10):1100-8. doi: 10.1016/S1470-2045(14)70379-1. Epub 2014 Aug 19) teaches a method of treating cancer comprising administration of 2000mg cilengitide twice weekly (which is recited in instant claim 34) with chemotherapy led to no clinical benefit compared to chemotherapy alone (Abstract): “…receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group)… None of the predefined clinical subgroups showed a benefit from cilengitide.”
Kim et al. (Int J Cancer. 2013 Aug 1;133(3):749-56. doi: 10.1002/ijc.28058) additionally examined methods of treating cancer with a combination of cilengitide and the chemotherapeutic belotecan, but found that cilengitide enhanced the activity of belotecan in treating glioblastoma and increased survival of U87MG tumor bearing subjects (Fig. 3 and 5):
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The prior art teaches that there is unpredictability in which combinations of integrin targeting agents combined with an immunotherapeutic or chemotherapeutic agent would lead to the treatment of cancer to enhance survival, as cilengitide enhances the effect of chemotherapy in some cases but has no effect in others.
Neither the instant specification nor the prior art discloses how to determine which peptide structures will have the function of “ αvβ3 and/or αvβ5 integrin targeting agent” and which will not, other that going through an iterative trial-and-error screening of libraries of different candidates to identify specific structures with this function. Additionally, neither the instant specification nor the prior art discloses how to distinguish which of these peptide structures would also be functional in methods of treating cancer in combination with different immunotherapies or chemotherapies.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of integrin binding agents falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 27-45 do not meet the requirements of 35 U.S.C. 112(a) for written description.
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 page 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 at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
To overcome this rejection, it is recommended to amend claim 27 to recite the specific αvβ3 targeting, αvβ5 targeting, and dual αvβ3 αvβ5 targeting agent structures the specification discloses with these functions and define their individual targets separately. Additionally, it is recommended to amend claim 27 to recite the specific integrin targeting structures and immunotherapeutic and/or chemotherapeutic structures that have been disclosed to treat cancer as a combination therapy.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 27-39 and 42-44 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 27 currently recites: “A method of treating a cancer in a patient, comprising administering an αvβ3- and/or αvβ5-integrin targeting agent and at least one immunotherapeutic agent and/or at least one chemotherapeutic agent to the patient.”
The claim is indefinite because it is currently unclear if the claim recites a method of treating cancer in a patient comprising: 1) administration of an αvβ3- and/or αvβ5-integrin targeting agent as well as either at least one immunotherapeutic agent and/or at least one chemotherapeutic agent to the patient; or 2) administration of an αvβ3- and/or αvβ5-integrin targeting agent as well as at least one immunotherapeutic agent, and/or at least one chemotherapeutic agent to the patient. The scope of the claim is currently unclear, as the second interpretation of the claim would lead it to encompass methods of treating cancer comprising administration of at least one chemotherapeutic and nothing else. Dependent claims 28-39 and 42-44 do not resolve this issue and are also rejected as indefinite.
For the purposes of examination, the claim has been interpreted to encompass methods comprising administration of an αvβ3- and/or αvβ5-integrin targeting agent as well as either at least one immunotherapeutic agent and/or at least one chemotherapeutic agent to the patient.
The recitation "derivative” in claims 34, 35, and 44 are indefinite because it is unclear what changes or how many changes could have occurred to result in a derivative. Derivation only describes the source and not the result. To overcome this, it is recommended to delete the term from the claims.
Claim 43 is additionally indefinite because the claim depends on claim 27 and recites: “…wherein the method further comprises administration of at least one chemotherapeutic agent.” However, instant claim 27 also recites “…and/or at least one chemotherapeutic agent…” It is currently unclear if the at least one chemotherapeutic recited in claim 43 is the same as the one recited in claim 27, or an additional “at least one chemotherapeutic”
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 43 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 43 depends from claim 27 and recites “…wherein the method further comprises administering at least one chemotherapeutic agent.” However, instant claim 27 already recites a method of treating cancer comprising administration of at least one chemotherapeutic agent: “…at least one chemotherapeutic agent to the patient.” The “at least one chemotherapeutic” recited in claim 43 falls within the scope of the “at least one chemotherapeutic” recited in claim 27.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 27-29, 31-34, and 43 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wong et al. (Cancer Cell. 2015 Jan 12;27(1):123-37. doi: 10.1016/j.ccell.2014.10.015).
Claim 27 recites a method of treating cancer comprising administration of an αvβ3 and/or αvβ5 targeting agent, as well as at least one immunotherapeutic and/or at least one chemotherapeutic.
Wong et al. teaches a method of treating cancer in a subject comprising administration of cilengitide and gemcitabine (Abstract): “…coadministration of low-dose Cilengitide and Verapamil increases tumor angiogenesis, leakiness, blood flow, and Gemcitabine delivery. This approach reduces tumor growth, metastasis, and minimizes side effects while extending survival.”
Wong et al. teaches that cilengitide is a αvβ3 and αvβ5 co-targeting integrin ligand (Introduction): “[c]ilengitide, an avb3/avb5 integrin-specific RGD-mimetic cyclic peptide…”. Wong et al. additionally teaches that gemcitabine is a chemotherapeutic (Introduction): “…some commonly used chemotherapeutics, such as Gemcitabine…”
Therefore, Wong et al. teaches a method of treating cancer comprising administration of the cyclic RGD motif containing Cilengitide and the chemotherapeutic Gemcitabine, anticipating the limitations of instant claims 27, 31, 32, and 34.
Regarding claim 28, Wong et al. teaches the combination therapy is effective against lung cancer (“Results”, Fig. 1): “C57/BL6 mice were injected subcutaneously with murine syngeneic Lewis lung carcinoma (LLC) cells…”
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Regarding claim 29, Wong et al. teaches that the combination therapy enhances patient survival in KPC tumors (Fig. 4G), meeting the claim limitations:
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Regarding claim 33, Cilengitide contains the RGD motif and therefore a Gly (claim 33(b)), meeting the claim limitations.
Regarding claim 43, Gemcitabine is a chemotherapeutic, meeting the claim limitations.
The reference teachings anticipate the invention encompassed by the instant claims.
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 27-34, and 40-45 are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (Cancer Cell. 2015 Jan 12;27(1):123-37. doi: 10.1016/j.ccell.2014.10.015, supra) in view of Sapalidis et al. (J Cancer. 2018 Apr 30;9(11):1973-1977. doi: 10.7150/jca.24782), as evidenced by Pan et al. (Bioengineered. 2022 Feb;13(2):4557-4572. doi: 10.1080/21655979.2022.2029236).
Claim 27 recites a method of treating cancer comprising administration of an αvβ3 and/or αvβ5 targeting agent, as well as at least one immunotherapeutic and/or at least one chemotherapeutic.
The teachings of Wong et al. have been discussed in the 35 U.S.C. § 102 rejection supra. Wong et al. does not teach a method of treating NSCLC such as LLC tumors in a subject comprising administration of cilengitide, an immunotherapeutic such as an anti-PD-1 antibody, as cisplatin (i.e., the limitations of instant claims 40-42, 44, and 45).
Sapalidis et al. teaches an aerosol pharmaceutical combination of the anti-PD-1 antibody nivolumab and the chemotherapeutic cisplatin to treat a mouse model of lung cancer (Abstract). Sapalidis et al. teaches that mice were inoculated with LLC lung cancer tumor cells and treated with the aerosol combination of nivolumab and cisplatin (“Mice” Section): “…Lewis lung carcinoma cell line was obtained by ATCC…[a]t confluence, cells were harvested with 0.25% trypsin and then were re-suspended at 1.5×106 cells in 0.15 ml PBS (Phosphate Buffered Saline, Dulbecco, Biochrom) which was injected in the left back foot of the mice. The foot was inoculated subcutaneously… mice were divided into five groups as follows: a) control group (no therapy), b) only aerosol nivolumab, c) only aerosol cisplatin, d) aerosol nivolumab and after three days aerosol cisplatin, e) aerosol cisplatin and after three days aerosol nivolumab.”
Sapalidis et al. additionally teaches the combination increases survival time and decreased lung metastases (pg. 1975, Fig. 2): “[m] Median survival: Group A) 15 days, Group B) 42 days, Group C) 39 days, Group D) 58 days and Group E) 51 days. In the control group most of the mice had lung cancer metastasis upon death. In Groups D and E only 7 mice had lung metastasis in total…”
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified combined the methods of treating cancer of Wong et al. and Sapalidis et al. with a reasonable expectation of success, as both references teach methods of treating lung cancer in as subject comprising administration of agents that one with ordinary skill in the art would easily be able to combine into one therapy, for example by administering all of the agents to one subject through the routes taught by Wong et al. and Sapalidis et al. One would have been motivated to make this change for the purposes of developing a more effective therapy for lung cancer.
Additionally, it is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; the idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
The combined therapy of Wong et al. and Sapalidis et al. comprise administration of the αvβ3/αvβ5 targeting agent cilengitide, cisplatin, and an anti-PD-1 antibody immunotherapeutic agent (i.e., the limitations of instant claims 40, 42, 44, and 45).
Regarding claims 30 and 41, Pan et al. is used as an evidentiary reference to demonstrate that these functional characteristics are inherent to the administered combination therapy of cilengitide and anti-PD-1 antibody therapy. Pan et al. teaches that addition of cilengitide to anti-PD-1 antibody therapy increases the number of CD8+ T-cells and the release of pro-inflammatory cytokines in tumors (i.e., “increases immune infiltration of the cancer”; Fig. 6):
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Furthermore, Pan et al. teaches that anti-PD-1 antibody therapy individually increases CD8+ T-cell infiltration modestly above control levels (i.e. “a CD8+ T-cell response”; see Fig. 6B). Therefore, in absence of evidence to the contrary, the functional characteristics of claims 30 and 41 are considered inherent to the therapy taught by the combined references.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 35-39 are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (supra) in view of Sapalidis et al. (supra), as evidenced by Pan et al. (supra) as applied to claims 27-34, and 40-45 above, and further in view of Weinmüller et al. (Angew. Chem. Int. Ed.2017, 56, 16405. doi: 10.1002/anie.201709709, supra).
The combined teachings of Wong et al. in view of Sapalidis et al., as evidenced by Pan et al. have been discussed supra. The combined teachings do not teach an αvβ3 and/or αvβ5 targeting agent comprising the prodrug structure of 29P (i.e., instant SEQ ID NO: 9), which are the limitations of instant claims 35-37.
Weinmüller et al., in the same field of endeavor, teaches that a limitation of the integrin targeting agent cilengitide is a lack of oral availability (Introduction): “[c]ilengitide was tested in phase III clinical trials for the treatment of glioblastoma…The peptide is not metabolized and totally stable in vivo…However, it is not orally available, a common limitation for most biologically active peptides.”
Weinmüller et al., teaches the development of the orally available αvβ3/ αvβ3 cyclic peptide 29 and the prodrug version 29P (pg. 16407): “[a]s a consequence of its high subnanomolar affinity for avb3 and selectivity, peptide 29, c(*vRGDA*A), was selected to be modified to its prodrug analogue 29P, c(*vR(Hoc)2GD(OMe)A*A) (Figure 2a), which is inactive in the ELISA tests to avb3 and a5b1.”
Weinmüller et al. teaches that cyclic peptide 29 has the same activity in tumors as other integrin targeting compounds such as cilengitide (pg. 16408): “[f]or the in vivo proof of oral availability, we first investigated the effect of the activation of tumor angiogenesis by using a low dose of 29P (orally) which will be cleaved into the avb3-active hexapeptide 29. The vascular endothelial growth factor (VEGF) is a potent pro-angiogenic factor and previous studies demonstrated that low doses of RGD peptides such as Cilengitide can enhance VEGF-mediated angiogenesis.[25] To test whether the cyclic hexapeptides developed here also possess this pro-angiogenic effect, different doses of 29 were initially evaluated ex vivo in aortic ring angiogenesis assays. Our data show that 0.2 nm and 2 nm doses of 29 significantly promote VEGF-stimulated microvessel sprouting.”
Weinmüller et al. further teaches that IP administered compound 29 has the same activity against LLC lung carcinoma tumors in vivo when compared with orally administered prodrug 29P, which is activated after entrance into the bloodstream (pg. 16408 and Fig. 3): “…treatment with orally administered 29P enhanced tumor blood vessel density and this was similar to the effect of administering the drug 29 IP…”
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Weinmüller et al. additionally teaches that 29P is an orally available integrin targeting prodrug with similar characteristics as cilengitide (pg. 16408): “[o]ur data indicate that hexapeptide 29 as well as the oral administration of its prodrug 29P have comparable effects to Cilengitide…”
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the combined teachings of Sapalidis et al., as evidenced by Pan et al., further in view of Weinmüller et al. to replace cilengitide with the prodrug compound 29P in the methods of treating lung cancer with a reasonable expectation of success, as Weinmüller et al. teaches 29P is an orally available integrin targeting agent that has similar effectiveness to cilengitide that one with ordinary skill in the art would be able to substitute to treat lung cancer such as LLC tumors, as the references all teach therapies to treat such lung cancer. One would have been motivated to make this change to allow for oral administration of the integrin targeting agent during cancer therapy, allowing for an easier and less invasive route of administration.
The combined references teach a method of treating lung cancer comprising administration of 29P (which is the modified cyclic hexapeptide c(*vR(Hoc)2GD(OMe)A*A)), cisplatin, and an anti-PD-1 antibody. The amino acids contained in 29P VRGDAA (albeit with many of the amino acids modified), which is instant SEQ ID NO: 28 (i.e., the limitations of instant claim 35):
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And the 29P peptide prodrug taught by Weinmüller et al. has the modification to the amino acids found in instant SEQ ID NO: 9, meeting the limitations of instant claim 36 and 37.
Regarding claim 38, Weinmüller et al. teaches oral administration of 29P (supra), meeting the claim limitations.
Regarding claim 39, Weinmüller et al. teaches treatment of cells with 29P in cell culture buffer (i.e., “an acceptable carrier, excipient, or diluent”; Supplemental material pg. 12): “…apical buffer containing 10 µg/ml 29 or 10 µg/ml 29P…”, meeting the claim limitations.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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