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 4/07/2026, is acknowledged.
Claims 2-81 are cancelled.
Claims 1 and 82-98 are currently pending.
Claims 1 and 93-98 are independent claims.
Election/Restrictions
Applicants’ election without traverse of Group I, claims 1, 93, 94, and 96-98, directed to a method of treatment comprising identifying a subject that has a TAA-expressing cancer and administering a cell comprising a fusion protein to a subject, and the Species of: i) the fusion protein of SEQ ID NO: 70, with the VH/VL of SEQ ID NO: 3 and 5, respectively, targeting the folate receptor α; ii) the fusion protein lacking SEQ ID NO: 2; iii) a human TIL; iv) 1x109 “CoStAR+ viable T cells”; and v) ovarian cancer, filed on 4/07/2026, is acknowledged.
Claims 96-98 are drawn to binding domains specific for unelected species of target.
Claims 95-98 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or Species.
Claims 1 and 82-94 are under examination as being drawn to identifying a subject that has a TAA-expressing cancer and administering a cell comprising a fusion protein to a subject.
Priority
Applicant’s claim for the benefit of a prior-filed U.S. Provisional Ser. No. 63/34582 1,filed May 25, 2022; U.S. Provisional Ser. No. 63/3697 19, filed July 28, 2022; U.S. Provisional Ser. No. 63/379534, filed October 14, 2022; and U.S. Provisional Ser. No. 63/49 1709 filed March 22, 2023, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/01/2023 and 12/13/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
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 drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Specifically, sequences appear in Fig. 67C and Fig. 68 without their corresponding sequence identifiers in the figures or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, 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 3 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Specifically, amino acid sequences appear in the specification at ¶[0161], [0454], [0467], and [0526].
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 lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The use of the terms:
PERCOLL™ (¶[0254]);
Dynabeads™ (¶[0394]);
CryoStor® (¶[0394]);
Cytofix/Cytoperm™ (¶[0398]);
Perm/Wash™ (¶[0398]);
xCELLigence® (¶[0416]);
RTCA® (¶[0416]); and
V-PLEX® (¶[0538]);
which are trade names or marks 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 Objections
Claim 1 recites the acronym “TIL”. This is not a readily recognized acronym in the art, such as “DNA” for 5’-deoxyribonucleic acid. Please define the acronym “TIL” when it is first used in the claims.
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 1 and 82-94 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 1 and 88-92 encompass a method of treating cancer in a subject that expresses a TAA comprising administration of a broad genus of fusion proteins with no recited structure and the function of “specific for the TAA”.
Claims 85-87 encompass a method of treating cancer in a subject that expresses a TAA comprising administration of a broad genus of fusion proteins with a partial structure at best and the function of “specific for the TAA”. Claim 85 recites VH structures without a corresponding VL structure, claim 86 recites VL structures without a corresponding VH structure, and claim 87 recites a genus of fusions proteins that comprise, for example, the elected species of SEQ ID NO: 70 and up to 15% sequence variation, including in the CDR regions critical for antigen binding.
Claims 83 and 84 encompass a method of treating cancer in a subject that expresses a TAA comprising administration of a fusion protein comprising the amino acid sequence structure in claim 83 or the CDR structures recited in claim 84, all with the function of “specific for the TAA”.
Claims 82, 93, and 94 encompass a method of treating cancer in a subject that expresses a TAA comprising administration of a broad genus of fusion proteins with no recited structure and the function of “specific for folate receptor α”.
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 “specific for the TAA” (claims 1 and 83-92) or “specific for FRα” (claims 82, 93, and 94).
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 the generation and use of CAR-T cells expressing a CAR that specifically binds a certain tumor-associated antigen (Example 1, Table 4). Each different CAR has an extracellular binding domain comprising HCDR1-3 and LCDR1-3 sequences (i.e., an antibody). The different extracellular binding domain sequences confer different target specificity to a certain tumor associated antigen (Table 4):
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For example, the extracellular domain found in ITIL-306 FRα specifically binds to FRα and not other tumor associated antigens.
The instant specification discloses one CAR extracellular binding domain structure that specifically binds to FRα, one structure that binds to PD-1, one structure that binds to CEA, and 6 structures that specifically bind to MSLN (Table 4). No examples of extracellular binding domains were given that bind to other TAAs, and the disclosed examples of extracellular binding domains each specifically bind to one target TAA antigen and not a generic “TAA”.
The instant specification discloses that these extracellular domain structures can be incorporated into CARs or CoStARs to target CAR-T cells to different antigens (Examples 1-5). For example, an anti-FRα CoStAR was used to target a CAR-T cell to FRα expressing tumor cells (Example 5). The different CoStAR protein structures (i.e., amino acid sequences) are also disclosed in Fig. 16 and 20-23.
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.).
The claims are directed to a genus of CARs comprising antibody extracellular binding domains with a partial structure at best and the functions of “specific for the TAA” (claims 1 and 83-92) or “specific for FRα” (claims 82, 93, and 94). However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
In the instant case, the application is claiming CARs comprising antibody extracellular binding domains, which comprise critical CDR regions that define specific binding to a particular epitope. The instant specification only discloses one CAR extracellular binding domain structure that specifically binds to FRα (i.e., “specific for FRα”), one structure that binds to PD-1, one structure that binds to CEA, and 6 structures that specifically bind to MSLN. No other representative species is disclosed that have the function of “specific for the TAA”, and no examples of CAR extracellular binding domains are given that can bind to a genus of TAAs to give rise to the function of “specific for the TAA”.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antigen binding constructs 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 antigen binding constructs, 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 at best describes a plan for making CoStARs comprising different extracellular antigen binding domains to target the proteins to specific targets or have the function of “specific for the TAA”, or “specific for FRα”, and then identifying those that satisfy the claim limitations, but a mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
The specification only discloses a limited number of antibody structures that are used as extracellular binding domains specific for different TAAs such as FRα. It is unlikely that antibodies or fragments thereof as defined by the claims which may contain less than the full complement of CDRs from the light and heavy variable regions of these antibody structures fused to framework sequences have the required binding function of “specific for FRα” The instant specification discloses no antibody structures that have the generic function of “specific for the TAA”. The specification provides no direction or guidance regarding how to produce antigen binding constructs with the functions of “specific for the TAA” or “specific for FRα” as broadly defined by the claims.
Additionally, the instant claim 87 encompass modifications to the claimed species of fusion proteins with up to 15% modifications to the amino acid sequences (insertions/deletions/substitutions), including in the claimed CDRs. There is no teaching identifying what amino acids can be varied within the HCDR1-3 or LCDR1-3 regions and still retain TCRs with the recited function of “specific for the TAA” or “specific for FRα”. It is known that even a single substitution of an amino acid within the CDR regions may significantly alter reactivity. Brown et al. (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. The scope of the claims encompasses antibodies with VH and VL regions that encompass variation (additions, deletions, substitutions) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of an antibody’s binding site, and thus when intact, would provide enough structure to define the antibody’s binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g., 6CDRs) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the alpha and beta chain variable regions of the disclosed antibody extracellular binding regions of CoStARs and the retention of the function of “specific for the TAA” or “specific for FRα” to satisfy the WD requirement for the claims.
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 CoStAR extracellular antigen binding domains 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 1 and 82-94 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 resolve this issue, it is recommended to amend claims 1, 93, and 94 to recite specific antibody structures, defined by their VH/VL or CDR sequences as well as the specific antigen to which the structure binds, that can be used as extracellular binding domains in CARs/CoStARs. For example, the binding domain specific for FRα comprising the HCDR1-3 and LCDR1-3 of SEQ ID NO: 79-84, respectively, or the sequence of an entire CoStAR such as SEQ ID NO: 70.
Claims 1 and 82-94 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 enablement requirement. The claims contain 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.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Breadth of claims and nature of invention:
Claims 1 and 82-94 encompass methods of treating cancer in a subject that expresses a generic TAA (claim 1 and 83-92) or FRα (claims 82, 93, and 94), comprising an antigen binding domain, a TM domain, a CD28 signaling domain, and a CD40 signaling domain.
The instant specification discloses the generation of T-cells expressing costimulatory antigen receptors (“CoStAR”), which releases IL-2 when the cell binds to its target antigen to stimulate local TIL activity (¶[0014]): “…administering a costimulatory antigen receptor ("CoStAR") to a subject in the absence of a level of IL-2, wherein the level of IL-2 is one sufficient to cause TIL stimulation in vivo when the CoStAR is absent.”
Fig 1 discloses the CoStAR elements, which include one transmembrane and signaling domains from both CD28 and CD40:
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The instant specification discloses how CoStAR molecules are used, in particular to enhance clonal expansion of anti-tumor T-cells. The specification discloses that T-cells are activated via two signals, one from the TCR/CD3 complex (signal 1), and a second costimulatory signal from a domain such as CD28 (¶[0008]): “…signal 1, provided by the TCR complex, synergizes with signal 2 provided by costimulatory receptors such as CD28, CD137 or CD134 to permit the cells to undergo clonal expansion, IL-2 production and long-term survival without the activation induced cell death (AICD) associated with signal I alone.”
The specification further discloses that CoStAR molecules provide the second, costimulatory signal upon recognition of the target receptor such as FRα to lead to local T-cell activation (¶[0234], [0238]): “…Signal 1 is provided by the native TCR. In some embodiments, Signal I is provided by an non-native TCR. In some embodiments, Signal 2 is provided by the fusion protein upon folate receptor alpha I binding. In some embodiments, Signal 2 is provided from CD28 and CD40 co-stimulatory domains. In some embodiments, Signal 2 is not provided by the fusion protein without signal 1 from the TCR/peptide/MHC interaction…stimulation of the fusion protein expressing cells involves recognition of cognate peptide presented on an MHC by a TCR (signal 1). In some embodiments a CoStAR of the invention is engineered not to provide signal 1. In some embodiments, a CoStAR of the invention does not comprise a signal 1 signaling domain.”
Amount of direction and existence of working examples:
Figure 18 discloses an example of how a CoStAR provides a co-stimulatory signal to a T-cells expressing TCRs:
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The instant specification discloses that T-cells transduced with an anti-CEA TCR, an anti-FRα CoStAR, or both had different activities against tumor cells that express both CEA and FRα (Example 5). Figure 7 discloses that T-cells expressing the CoStAR molecule alone does not reduce tumor cell growth over time, while only T-cells co-expressing both the anti-CEA TCR and anti-FRα CoStAR consistently reduced in vitro tumor cell growth over time (“TCR.CoStAR-Td”):
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In an in vivo model of tumor growth, T-cells expressing an anti-CEA TCE, an anti-FRα CoStAR, and both receptors were administered to a subject in the presence and absence of IL-2. In all cases, only cells expressing both the TCR and CoStAR receptors significantly delayed tumor growth (Fig. 15):
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Another in vivo model of tumor growth demonstrated similar results, tumor reduction in the presence and absence of IL-2 occurred when T-cells co-expressing an anti-CEA TCR and an anti-FRα CoStAR were administered to subjects with CEA/FRα expressing tumor cells:
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Additionally, the instant specification discloses isolation of tumor-infiltrating lymphocytes (TILs) from ovarian, renal, and non-small cell lung cancer, followed by transduction of lentiviral particles to allow the TILs to express an anti-FRα CoStAR (¶[0477]): “…we developed a lentiviral transfer protocol to deliver CoStAR to patient derived TIL with high efficiency. TIL from five ovarian, four renal, and four lung tumor samples were successfully transduced with lentiviral particles…” The transduced TILs produced greater amounts of IFN-γ when exposed to digests of the tumor in which the TILs were isolated from (Fig. 44B):
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¶[0479]: “…CoStAR enhanced anti-tumor activity across multiple FRa expressing tumors”.
The instant specification further confirms that anti-FRα CoStAR expressing T-cells do not have cytolytic activity unless there is the initial signal from a TCR or CD3 signaling domain (¶[0521]): “[a]s previously demonstrated, the anti-FRa CoStAR molecule is designed to exclusively provide costimulation and is not expected to induce cytolytic activity in the absence of TCR activation i.e., signal 1.” (¶[0531]): “[a]nti-FRa CoStAR enhances T-cell function in response to target antigen regardless of the degree of FRa expression. CoStAR does not respond to FRa in the absence of TCR stimulation ( cytokine production or cytotoxicity ), even at physiologically high levels of Fra…”
Level of predictability, state of prior art, and quantity of experimentation needed:
The instant claims are directed to a method of treating a cancer in a subject that has a cancer expressing a TAA comprising administration of a cell comprising a fusion protein comprising a binding domain specific for the TAA, a TM domain, a CD28 signaling domain, and a CD40 signaling domain, i.e. a CoStAR (claims 1 and 83-90), wherein the cell is a generic TIL (claims 91 and 94), or wherein the cancer is ovarian cancer (claim 92), or wherein the TAA is FRα (claims 82, 93, and 94). Instant claims 83 and 87 recite the method of treatment comprising administration of cells expressing specific CAR sequences and/or variants thereof.
However, the instant specification discloses that a cell comprising a CoStAR will have no effect on treating cancer. Additionally, the instant specification discloses that an engineered cell needs to express a CoStAR comprising an extracellular domain that binds to one specific TAA on a specific tumor (i.e., FRα) as well as expressing a second protein, such as a TCR, that is reactive to a different antigen on the specific tumor to be treated (i.e., CEA).
Regarding claims 1 and 83-90, and 92-94, the instant specification discloses an example of treating a FRα and CEA expressing tumor in a subject comprising administration of T-cells engineered to express a specific anti-CEA TCR structure (defined by its amino acid sequence), as well as a specific anti-FRα CoStAR structure (defined by its amino acid sequence). Other CoStAR structures, defined by their amino acid sequences, are also disclosed to target different antigens such as CEA and MSN. There is no guidance in the instant specification nor in the prior art to enable one with ordinary skill in the art to make and use a method of treating cancer in a subject expressing a generic TAA (i.e., any and all TAAs) comprising administration of a cell comprising only a CoStAR with a generic extracellular binding domain. In fact, the instant specification teaches that a cell such as a T-cell expressing only a CoStAR does not reduce tumor growth. Undue experimentation would be required to make and use this broadly claimed method of treating any cancer expressing any TAA comprising administration of a cell comprising a CoStAR.
Regarding claims 91 and 94, the instant specification discloses that harvesting TILs from a specific tumor (i.e., NSCLC, ovarian cancer, and renal cancer) and inducing expression of a CoStAR in this population of tumors, followed by in vitro contacting of these transduced TILs administration of this transduced population with their autologous tumors (see Fig 44B supra and Fig. 69 below):
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The CoStAR extracellular binding domain was against FRα, which all three tumor samples expressed. Neither the instant specification nor the prior art disclose methods of treating any cancer expressing any TAA, or FRα, comprising administration of any TIL (autologous or non-autologous) comprising a CoStAR comprising a binding domain that is specific for any TAA/FRα (i.e., the limitations of instant claims 91 and 94). For example, the instant specification does not disclose if the transduced TILs harvested from NSCLC were efficacious in treating ovarian cancer cells (both of which express FRα). Undue experimentation would be required to use the broadly claimed methods of treating cancer in a subject.
Regarding the elected species of fusion protein SEQ ID NO: 70 (claims 83 and 87); the fusion protein represented by the sequence has multiple transmembrane domains (see bold and underlined sequence below; this is the CD28 TM domain represented by instant SEQ ID NO: 9):
QVQLQQSGAELVKPGASVKISCKASGYSFTGYFMNWVKQSHGKSLEWIGRIHPYDGDTFYNQNFKDKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIELTQSPASLAVSLGQRAIISCKASQSVSFAGTSLMHWYHQKPGQQPKLLIYRASNLEAGVPTRFSGSGSKTDFTLNIHPVEEEDAATYYCQQSREYPYTFGGGTKLEIKAAAGSGGSGILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ
The instant specification provides guidance on making and using such CoStAR molecules that have one TM domain. Instant Figs. 1 and 26 demonstrate examples of such fusion proteins with one TM domain and, for example, instant Fig. 69 demonstrates that CoStAR molecule with one TM domain function properly when expressed in a cell, allowing a TIL expressing the CoStAR to increase IFNγ levels when the TIL comes in contact with TAA expressing tumor cells.
However, neither the instant specification nor the prior art provides guidance on whether or not costimulatory antigen receptors with two transmembrane domains would function properly when expressed in a cell such as a TIL. Undue experimentation would be required by one with ordinary skill in the art to determine whether or not costimulatory antigen receptors with two separate TM domains would function the same as CoStAR molecules with only one TM domain in methods of treating cancer expressing a TAA.
Regarding the claims 88 and 89, Geldres et al. (Semin Immunol. 2016 Feb;28(1):3-9. doi: 10.1016/j.smim.2015.12.001) teaches that signal peptides are a necessary component of chimeric antigen receptors/CoStARs (Section 1.1.1): “[t]he native signal peptide of a protein is an N-terminal short sequence necessary for the translocation of the nascent precursor protein to the endoplasmic reticulum membrane and to the secretory pathway… the signal peptide is added “ectopically” to the scFv for the CAR assembling, and different sequences have been used.”
The prior art teaches that signal peptides are necessary for proper subcellular trafficking of a CoStAR to the plasma membrane. Undue experimentation would be required by one with ordinary skill in the art to make and use a methods of treating cancer comprising administration of a cell comprising a CoStAR without the signal peptide sequence, as it would not be known if the receptor is expressed on the plasma membrane and therefore able to bind to TAAs.
The specification does not reasonably provide enablement to use the invention of claims 1 and 82-94 as they are currently written.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
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 88 is 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 88 recites the limitation "the signal peptide sequence" in lines 1 and 2. There is insufficient antecedent basis for this limitation in the claim, as claim 88 depends on claim 1, and claim 1 does not recite the limitation “signal peptide”. For the purposes of examination, claim 88 is interpreted to recite the limitation “The method of claim 1, wherein the fusion protein lacks a signal peptide sequence”.
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 1, 82, 84-86, 92, and 93 are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by Bridgeman et al. (WO2022016112), as evidenced by Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72. doi: 10.3390/ph10030072).
Independent claim 1 claims a method of treating cancer in a subject that expresses a TAA comprising administration of a cell comprising a fusion protein comprising a binding domain specific for a TAA, a TM domain, a CD28 signaling domain, and a CD40 signaling domain; wherein the subject also does not receive exogenous IL-2 to stimulate TILs in vivo. Independent claim 93 recites the same method of treatment as claim 1, however the TAA is limited to FRα. Independent claim 94 recites the same method of treatment as claim 94, however the cell comprises a tumor infiltrating lymphocyte (TIL).
Bridgeman et al. has a publication date of 1/20/2022, and a filing date of 7/7/2020, both of which are prior to the effective filing date of the instant application (5/25/2022).
Bridgeman et al. teaches costimulatory antigen receptors (CoStARs) comprising an extracellular binding domain specific to a tumor associated antigen (TAA) linked to a TM domain, linked to a CD28 signaling domain, linked to a CD40 signaling domain (claim 1). Bridgeman et al. additionally teaches that the TAA can be FRα (claim 2), and the extracellular binding domain comprises a MOV19 scFv (claim 3).
Bridgeman et al. additionally teaches methods of treating cancer comprising identifying mice subjects with SK-OV-3 tumors followed by administration of human T-cells expressing an anti-FRα (aka FOLR1) CoStAR (¶[00305]): “…primary human T-cells are mock transduced or transduced with MOV19.CD28.CD40 CoStAR construct followed by in vitro expansion and cryopreservation. MOV1 9 is a single chain Fv antibody that has a high affinity for Folate Receptor alpha (FOLRl). Immunocompromised mice are implanted with an established ovarian cancer cell line (A2870, OVCAR-5, OVCAR-8 or SK-OV-3), which is allowed to grow in the animal for few days. Mice are subsequently staged according to their tumor burden, and finally injected with the mock transduced T cells or MOV19.CD28.CD40 transduced T cells…”
Bridgeman et al. further teaches some of the subjects do not receive exogenous IL-2 (¶[00305], emphasis added): “[t]he final study design contains 5 groups (each one containing 5 mice): PBS (no cells dosed), mock transduced T cells, mock transduced T cells with IL-2 supplementation, MOV19.CD28.CD40 transduced T cells and MOV19.CD28.CD40 transduced T cells with IL-2 supplementation.”
Siwowska et al. is provided as an evidentiary reference to demonstrate that SK-OV-3 cells express FRα/FOLR1 (Abstract): “…FR-expressing human cancer cell lines—including cervical (HeLa, KB, KB-V1), ovarian (IGROV-1, SKOV-3, SKOV-3.ip)…”
Therefore, Bridgeman et al. teaches a method of treating ovarian cancer in a subject comprising identifying a subject that has a SK-OV-3 cancer that expresses the FRα TAA, followed by administration of an anti-FRα CoStAR, wherein the subject does not receive exogenous IL-2, anticipating instant claims 1, 82, 92, and 93.
Regarding claims 84-86, Bridgeman et al. teaches an anti-FRα CoStAR comprising the anti-FRα scFv extracellular domain of sequence of SEQ ID NO: 4, which is 100% identical to the scFv in instant SEQ ID NO: 70 (i.e., “the CDRs of SEQ ID NO: 70”):
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SEQ ID NO: 4 of Bridgeman et al. also comprises the VH of instant SEQ ID NO: 3:
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SEQ ID NO: 4 of Bridgeman et al. also comprises the VL of instant SEQ ID NO: 5:
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This meets the claim limitations of instant claims 84-86.
The reference teachings anticipate the instantly claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 82, 84-86, and 88-94 are rejected under 35 U.S.C. 103 as being unpatentable over Bridgeman et al. (WO2022016112, supra) in view of Ikarashi et al. (Cancer Res. 1994 Jan 1;54(1):190-6), as evidenced by Siwowska et al. (Pharmaceuticals (Basel). 2017 Aug 15;10(3):72. doi: 10.3390/ph10030072, supra)
The teachings of Bridgeman et al., as evidenced by Siwowska et al., has been discussed in the 35 U.S.C. § 102 rejection supra. Bridgeman et al., as evidenced by Siwowska et al., does not teach a method of treating a TAA expressing cancer comprising administration of a TIL expressing an anti-FRα CoStAR (i.e., the limitations of instant claims 91 and 94).
Ikarashi et al., in the same field of endeavor, teaches a method of treating human subjects with epithelial ovarian cancer comprising adoptive transfer (i.e., “administration”) of tumor infiltrating lymphocytes (i.e., “identifying a subject in need of TIL therapy”; Abstract): “…12 patients with epithelial ovarian cancer who received adoptive transfer of tumor-infiltrating lymphocytes (TILs) after cisplatin containing chemotherapy (TIL group). As a control, 10 patients with epithelial ovarian cancer who did not receive infusions of TIL were also examined in the same fashion…”.
Ikarashi et al. further teaches the method comprises isolating human TILs from cancerous tissue from patients, cultured ex vivo and then re-administered to patients with the autologous cancer as adoptive cellular therapy (“Treatment Design” and “Culture and Infusion of TILs” Section). Ikarashi et al. further teaches that the patients were no administered exogenous IL-2 (“Treatment Design” Section): “rIL-2 was used only for TIL cultivation and was not administered to the patients”. Ikarashi et al. teaches that out of 12 patients receiving adoptive TIL therapy, 11 had no evidence of disease (Table 2):
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Ikarashi et al. further teaches (Discussion): “[w]ith a median follow-up time of 26.5 months (range, 22-33 months), the 2-year survival rate for the TIL group is 100% by the Kaplan-Meier method, whereas it has been reported that the 2-year survival rate for patients with progressive common epithelial ovarian cancer is 47-63% (34-36). Therefore, the protocol of this study may be effective to improve survival rate.”
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 teachings of Bridgeman et al., as evidenced by Siwowska et al., in view of Ikarashi et al. to use autologous human TILs as the cells in the method of treating ovarian cancer taught by Bridgeman et al. with a reasonable expectation of success (i.e., the limitations of instant claims 91 and 94), as Bridgeman et al. teaches that the cells expressing CoStARs can be TILs (claim 47). Additionally, one with ordinary skill in the art would appreciate that the method of treatment taught by Bridgeman et al. can be expanded to humans, especially in view of Ikarashi et al., which teaches use of autologous human TILs to treat ovarian cancer in humans. One would have been motivated to make this change for the purposes of using autologous TILs expressing CoStARs against ovarian cancer TAAs such as FRα to treat ovarian cancer in human subjects to improve survival rate, as suggested by Ikarashi et al.
Regarding claims 88 and 89, the instant claims recite methods of treatment wherein the CoStAR fusion protein lacks a signal peptide sequence (claim 88), or specifically SEQ ID NO: 2, which is the Oncostatin M signal peptide (see Fig. 16). Bridgeman et al. teaches (claim 41): “[t]he CoStAR of any one of claims 1 to 37, which further comprises an N-terminal signal peptide”. Given that Bridgeman et al. teaches that the CoStAR can further comprise a signal peptide, then Bridgeman et al. also teaches the CoStAR without a signal peptide at all (for example, the CoStARs taught in claims 1-37), as well as methods of treating cancer expressing a TAA. The CoStAR without a signal peptide sequence meets the limitations of instant claims 88 and 89.
Regarding claim 90, Ikarashi et al. teaches that the patients are administered 1x109 TIL cells in the method of treatment (“Culture and Infusion of TILs” section): “[a]fter 5 weeks of cultivation (3 weeks before freezing and 2 weeks after thawing), the number of cells exceeded 1 x 109. The TILs in 100 ml of sterile saline supplemented with 20 ml of 25% albumin were administered i.v. to patients for 15-30 min at one time. Twelve patients whose number of cells reached 1 x 109 by the injection were selected for further investigation”, and the combined references of Bridgeman et al. in view of Ikarashi et al., as evidenced by Siwowska et al. teach administration of this number of TILs induced to express the anti-FRα CoStAR, 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.
Claims 1, 82, 84-86, and 88-94 are rejected under 35 U.S.C. 103 as being unpatentable over Ikarashi et al. (supra) in view of WO2020152451, as evidenced by Ab et al. (WO2011106528).
Ikarashi et al. teaches a method of treating subjects with epithelial ovarian cancer comprising adoptive transfer (i.e., “administration”) of tumor infiltrating lymphocytes (i.e., “identifying a subject in need of TIL therapy”; Abstract): “…12 patients with epithelial ovarian cancer who received adoptive transfer of tumor-infiltrating lymphocytes (TILs) after cisplatin containing chemotherapy (TIL group). As a control, 10 patients with epithelial ovarian cancer who did not receive infusions of TIL were also examined in the same fashion…”.
Ikarashi et al. further teaches the method comprises isolating human TILs from cancerous tissue from patients, cultured ex vivo and then re-administered to patients with the autologous cancer as adoptive cellular therapy (“Treatment Design” and “Culture and Infusion of TILs” Section). Ikarashi et al. further teaches that the patients were no administered exogenous IL-2 (“Treatment Design” Section): “rIL-2 was used only for TIL cultivation and was not administered to the patients”. Ikarashi et al. teaches that out of 12 patients receiving adoptive TIL therapy, 11 had no evidence of disease (Table 2, supra).
Ikarashi et al. further teaches (Discussion): “[w]ith a median follow-up time of 26.5 months (range, 22-33 months), the 2-year survival rate for the TIL group is 100% by the Kaplan-Meier method, whereas it has been reported that the 2-year survival rate for patients with progressive common epithelial ovarian cancer is 47-63% (34-36). Therefore, the protocol of this study may be effective to improve survival rate.”
Therefore, Ikarashi et al. teaches a method of treating ovarian cancer in a subject comprising administration of human TILs, wherein the subject does not receive exogenous IL-2.
Ikarashi et al. does not teach administration of the TILs comprising a CoStAR (i.e., the limitations of instant claim 1).
WO20201524501, in the same field of endeavor teaches chimeric costimulatory receptors (“CoStARs”; Fig.1):
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WO2020152451 further teaches an anti-FRα comprising the MOV-19 scFv and the CD28/CD40 signaling domains expressed in human T cells harvested from donors (¶[00159]-[00160]): “[p]rimary T-cells from three donors were transduced with either the CD28(IEV) truncated CoStAR, full length CD28 CoStAR or CD28.CD40 CoStAR (having the full length CD28 as shown in SEQ ID NO. 10, but lacking the N terminal N and K residues) or left non-transduced… T-cells from seven donors were transduced with either CD28 or CD28.CD40 CoStARs with either an antiCA125 (196-14) or anti-Folate receptor (MOV-19) scFv…”
SEQ ID NO: 10 of WO2020152451 is the following:
NKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ
Removing the N-terminal N and K residues gives the following:
ILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ
WO2020152451 further teaches the sequences of the different domains of CD28 (pg. 53):
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Thus, SEQ ID NO: 10 of WO2020152451 without the N-terminal N and K residues comprises the CD28 protein extracellular/spacer portion, linked to the CD28 TM domain, linked to the CD28 intracellular domain, linked to the CD40 intracellular domain (see annotated SEQ ID NO: 10 below, underlined is CD28 portion):
ILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ
Therefore, WO2020152451 teaches T-cells expressing CoStARs comprising the MOV-19 scFv fused to SEQ ID NO: 10 without the N-terminal N and K residues.
WO2020152451 further teaches that the anti-FRα CoStAR expressed on cells binds to ovarian cancer cells and leads to T-cell expansion through receptor activation (¶[00160]): “[c]ells were then mixed with CA125+/Folate receptor+/CEA- cell line OvCAR3…Limited expansion of cells harbouring the anti-CA125 scFv was observed (mean fold expansion: CD28: 15.1; CD28.CD40: 69.1), however cells targeting Folate receptor with an scFv did expand in both the CD28 and CD28.CD40 cohorts…”
WO2020152451 additionally teaches the CD28/CD40 stimulatory domains lead to enhanced effector activity of T-cells (¶00161]): “[t]hus CD28.CD40 shows enhanced effector activity across a broad range of models and effector activities.”
WO2020152451 further teaches methods of transducing T-cells to engineer them to express the CoStAR (claims 1, 13-16, 19, and 20).
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 teachings of Ikarashi et al. in view of WO2020152451 to transduce the TILs of Ikarashi et al. with a mov-19 anti-FRα CD28.CD40 CoStAR taught by WO2020152451 with a reasonable expectation of success, as WO2020152451 teaches methods of transducing T-cells to express the CoStARs. One would have been motivated to make this change for the purpose of engineering the TILs of Ikarashi et al. to express an anti-FRα CoStAR to enhance the effector activity of the TILs in treating ovarian cancer.
The method of the combined teachings is a method of treating ovarian cancer in a subject, which expresses FRα (WO2020152451 teach that ovarian cancer cells express FRα, see supra), comprising administration of autologous human TILs engineered to express (i.e., “comprising”) a CoStAR comprising a Mov-19 anti-FRα scFv, a TM domain, and the CD28.CD40 signaling domains, wherein the subject does not receive exogenous IL-2, meeting the limitations of instant claims 1, 82, and 91-94.
Regarding claims 84-86, Ab et al. is provided as an evidentiary reference to demonstrate that the VH/VL sequences of Mov19, which is 100% identical to the elected species of VH/VL (¶[0108]): “…FOLR-1 binding agents are humanized versions of the murine Mov19 antibody (variable heavy and light chain shown as SEQ ID NOs: 17 and 18 respectively…”. Ab et al. further teaches the antibody can be in scFv form (claim 68). SEQ ID NO: 17 of Ab et al. is 100% identical to instant SEQ ID NO: 3:
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SEQ ID NO: 18 of Ab et al. is 100% identical to instant SEQ ID NO: 5:
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The VH and VL of the mov-19 antibody are the VH and VL of the scFv in instant SEQ ID NO: 70 and therefore have the CDRs in this sequence, meeting the claim limitations:
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Regarding claims 88 and 89, WO2020152451 does not teach that the anti-FRα CoStAR comprises a signal peptide (see, for example, Fig. 2 and claims 1-5), and in absence to evidence to the contrary a signal peptide is presumed to be absent, meeting the claim limitations.
Regarding claim 90, Ikarashi et al. teaches that the patients are administered 1x109 TIL cells in the method of treatment (“Culture and Infusion of TILs” section): “[a]fter 5 weeks of cultivation (3 weeks before freezing and 2 weeks after thawing), the number of cells exceeded 1 x 109. The TILs in 100 ml of sterile saline supplemented with 20 ml of 25% albumin were administered i.v. to patients for 15-30 min at one time. Twelve patients whose number of cells reached 1 x 109 by the injection were selected for further investigation”, and the combined references of Ikarashi et al. in view of WO2020152451, as evidenced by Ab et al. teach administration of this number of TILs induced to express the anti-FRα CoStAR, 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 88, 89, and 91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,945,876 (Pat ‘876) in view of WO2020152451. Although the claims at issue are not identical, they are not patentably distinct from each other.
Pat ‘876 claims methods of cell therapy (i.e., “treating cancer”) comprising identifying a subject, wherein the subject has a CEA expressing cancer (i.e. “in need of TIL cell therapy”) and administering a TIL expressing an anti-CEA CoStAR (claim 14). Pat ‘876 further claims the anti-CEA CoStAR comprises an extracellular binding domain specific for CEA (i.e., “a TAA”), linked to an ICOS signaling domain, linked to a CD40 signaling domain.
Pat ‘876 does not claim methods in which the CoStAR comprises a CD28 signaling domain (i.e., the limitations of instant claims 1, 91 and 94)
WO2020152451, in the same field of endeavor, teaches a CD28.CD40 signaling domain used in CoStARs to treat cancer (¶[00160]): “…T-cells from seven donors were transduced with either CD28 or CD28.CD40 CoStARs with either an antiCA125 (196-14) or anti-Folate receptor (MOV-19) scFv…Cells were then mixed with CA125+/Folate receptor+/CEA- cell line OvCAR3…cells targeting Folate receptor with an scFv did expand in both the CD28 and CD28.CD40 cohorts…”
WO2020152451 further teaches (¶[00161]): “…CD28. CD40 shows enhanced effector activity across a broad range of models and effector activities.”
It would have been obvious to one with ordinary skill in the art to have modified the invention claimed by Pat ‘876 in view of WO2020152451 to have used the CD28.CD40 signaling domains in the anti-CEA CoStAR claimed by Pat ‘876 (i.e., the limitations of instant claims 1 and 94) in the method of treating cancer with a reasonable expectation of success, as WO2020152451 teaches this signaling domain can be used in CoStARs, including anti-CEA CoStARs (WO2020152451 claims 1-5). One would have been motivated to make this change for the purposes of increasing the efficacy of the CoStAR claimed by Pat ‘876.
Regarding the functional language “wherein the subject does not receive exogenous IL-2”; the method claimed by Pat ‘876 does not comprise administration of IL-2, meeting the limitations.
Regarding claims 88 and 89, Pat ‘876 claims the CoStAR fusion protein lacking a signal peptide (claim 9), and further comprising the signal peptide (claim 10). One with ordinary skill in the art would appreciate that the CoStAR without a signal peptide would also not contain the signal sequence of instant SEQ ID NO: 2, meeting the claim limitations.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘876 in view of WO2020152451, especially in absence of evidence to the contrary.
Claims 90 and 92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,945,879 (Pat ‘876) in view of WO2020152451, as applied to claims 1, 88, 89, and 91 above, and further in view of Ikarashi et al. (Cancer Res. 1994 Jan 1;54(1):190-6, supra) and Juweid et al. (J Nucl Med. 1997 Feb;38(2):257-60. PMID: 9025751). Although the claims at issue are not identical, they are not patentably distinct from each other.
The combined teachings of Pat ‘876 in view of WO2020152451 are discussed supra. Pat ‘876 in view of WO2020152451 does not claim methods of treating ovarian cancer, or administration of 1x109 CoStAR cells (i.e., the limitations of instant claims 90 and 92).
Juweid et al., in the same field of endeavor, teaches that CEA is a target biomarker for ovarian cancer (Abstract), teaches that ovarian cancers express CEA (pg. 257): “[o]varian cancer is known to produce carcinoembryonic antigen (CEA), and the plasma CEA level is frequently elevated in patients with advanced stage and amount of tumor (2,3). Moreover, Goldenberg and associates have reported a high CEA content, ranging from 115 to 17,800 ng/g in malignant ovarian tumors, even when the plasma CEA level was normal (4). These findings are consistent with reports of other investigators that tumors manufacturing CEA do not necessarily secrete it into the circulation”
Juweid et al. further teaches that anti-CEA therapy can treat ovarian cancer, as an anti-CEA antibody fused to a radioisotope was able to treat ovarian cancer in a human patient (Abstract): “[a] complete clinical remission, using two cycles of 131l-labeled murine MN-14 anti-CEA monoclonal antibody (MAb),given intravenously, is reported in a patient with advanced ovarian cancer refractory to paclitaxel…”
Ikarashi et al., in the same field of endeavor, teaches that TIL therapy for ovarian cancer without addition of exogenous IL-2 can be effective when 1x109 TILs are administered (“Culture and Infusion of TILs” section): “[a]fter 5 weeks of cultivation (3 weeks before freezing and 2 weeks after thawing), the number of cells exceeded 1 x 109. The TILs in 100 ml of sterile saline supplemented with 20 ml of 25% albumin were administered i.v. to patients for 15-30 min at one time. Twelve patients whose number of cells reached 1 x 109 by the injection were selected for further investigation”. (Discussion): “[w]ith a median follow-up time of 26.5 months (range, 22-33 months), the 2-year survival rate for the TIL group is 100% by the Kaplan-Meier method, whereas it has been reported that the 2-year survival rate for patients with progressive common epithelial ovarian cancer is 47-63% (34-36). Therefore, the protocol of this study may be effective to improve survival rate.”
It would have been obvious to one with ordinary skill in the art to have modified the invention claimed by Pat ‘876 in view of WO2020152451 further in view of Ikarashi et al. and Juweid et al. to use anti-CEA CoStAR therapy to treat ovarian cancer comprising administration of 1x109 cells (i.e., the limitations of instant claims 90 and 92) with a reasonable expectation of success, as Juweid et al. teaches that ovarian cancer expresses CEA and therapy targeting CEA can be effective to treat ovarian cancer, and Ikarashi et al. teaches that 1x109 TILs is an effective number to treat ovarian cancer. One would have been motivated to make this change for the purposes of developing a method of treating ovarian cancer with CoStAR TILs.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘876 in view of WO2020152451, and further in view of Ikarashi et al. and Juweid et al., especially in absence of evidence to the contrary.
Claims 1 and 88-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 12,187,778 (Pat ‘778) in view of Scholler et al. (Biomark Med. 2007 Dec;1(4):513-23. doi: 10.2217/17520363.1.4.513) and Ikarashi et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
Pat ‘778 claims CoStAR molecules comprising the antibody 196-14 in scFv format linked to a TM domain, linked to CD28 and CD40 signaling domains (claim 1), which is specific for CA125 (claim 10). Pat ‘778 additionally claims nucleic acids encoding the CoStAR and cells expressing the CoStAR (claims 11 and 12).
Pat ‘778 does not claim methods of treating cancer, such as ovarian cancer comprising identifying a subject that has a cancer expressing a TAA such as CA125 or that is in need of TIL therapy and administration of the cells expressing the CoStAR, wherein the subject does not receive exogenous IL-2 (i.e., the limitations of instant claim 1).
Scholler et al., in the same field of endeavor, teaches that CA125 is one of the earliest biomarkers for ovarian cancer (Introduction). Scholler et al. further teaches that CA125 is a target for cancer therapy (pg. 6): “[b]iologic therapies for EOC are being developed and ongoing clinical trials are investigating the use of CA125 as a target for immunotherapy.” (Conclusion): “…CA125 represents an attractive therapeutic target and numerous groups have been developing various approaches…”
Ikarashi et al., in the same field of endeavor teaches a method of treating subjects with epithelial ovarian cancer comprising adoptive transfer (i.e., “administration”) of tumor infiltrating lymphocytes (i.e., “identifying a subject in need of TIL therapy”; Abstract): “…12 patients with epithelial ovarian cancer who received adoptive transfer of tumor-infiltrating lymphocytes (TILs) after cisplatin containing chemotherapy (TIL group). As a control, 10 patients with epithelial ovarian cancer who did not receive infusions of TIL were also examined in the same fashion…”.
Ikarashi et al. further teaches the method comprises isolating TILs from cancerous tissue from patients, cultured ex vivo and then re-administered to patients with the autologous cancer as adoptive cellular therapy (“Treatment Design” and “Culture and Infusion of TILs” Section). Ikarashi et al. further teaches that the patients were no administered exogenous IL-2 (“Treatment Design” Section): “rIL-2 was used only for TIL cultivation and was not administered to the patients”. Ikarashi et al. teaches that out of 12 patients receiving adoptive TIL therapy, 11 had no evidence of disease (Table 2, supra).
Ikarashi et al. further teaches (Discussion): “[w]ith a median follow-up time of 26.5 months (range, 22-33 months), the 2-year survival rate for the TIL group is 100% by the Kaplan-Meier method, whereas it has been reported that the 2-year survival rate for patients with progressive common epithelial ovarian cancer is 47-63% (34-36). Therefore, the protocol of this study may be effective to improve survival rate.”
Therefore, Ikarashi et al. teaches a method of treating ovarian cancer in a subject comprising administration of TILs, wherein the subject does not receive exogenous IL-2.
It would have been obvious to one with ordinary skill in the art to have modified the invention claimed by Pat ‘778 in view of Scholler et al. and Ikarashi et al. to have used the anti-CA125 CoStAR expressed on TILs to treat ovarian cancer with a reasonable expectation of success, as Pat ‘778 claims such CoStARs and cells expressing the fusion polypeptide, Scholler et al. teaches that CA125 is an attractive target for ovarian cancer, and Ikarashi et al. teaches a method of administration of TILs to treat ovarian cancer. One would have been motivated to make this change for the purposes of developing a CoStAR treatment for ovarian cancer.
The combined references teach a method of treating CA125 expressing ovarian cancer comprising identifying a subject with ovarian cancer that expressing CA125 and administration of TILs expressing an anti-CA125 CoStAR, wherein the subject does not receive exogenous IL-2, meeting the limitations of instant claims 1, 91 and 92.
Regarding claims 88 and 89, Pat ‘778 claims CoStARs lacking a signal peptide sequence (claim 1), meeting the claim limitations.
Regarding claim 90, Ikarashi et al. teaches that the patients are administered 1x109 TIL cells in the method of treatment (“Culture and Infusion of TILs” section): “[a]fter 5 weeks of cultivation (3 weeks before freezing and 2 weeks after thawing), the number of cells exceeded 1 x 109. The TILs in 100 ml of sterile saline supplemented with 20 ml of 25% albumin were administered i.v. to patients for 15-30 min at one time. Twelve patients whose number of cells reached 1 x 109 by the injection were selected for further investigation”, and the combined references of Pat ‘778 in view of Scholler et al. and Ikarashi et al. teach administration of this number of TILs induced to express the anti-CA125 CoStAR, meeting the claim limitations.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘876 in view of Scholler et al. and Ikarashi et al., especially in absence of evidence to the contrary.
Claims 1, 82, and 88-94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 36, 38, 40-46, 48, and 51-68 of co-pending Application No. 17/361,621 (App ‘621) in view of Armstrong et al. (Gynecol Oncol. 2013 Jun;129(3):452-8. doi: 10.1016/j.ygyno.2013.03.002) and Ikarashi et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘621 claims CoStARs comprising an extracellular domain that binds to a TAA linked to a transmembrane domain, linked to a CD28 signaling domain, linked to a CD40 signaling domain (claims 36 and 41). App ‘621 further claims the CoStAR ECD is specific for FRα (claim 53), as well as cells comprising the CoStAR (claim 61), and methods of treating a disease comprising administration of the CoStAR expressing cell (claim 64), including cancer (claim 65), and human subjects (claim 66).
App ‘621 does not claim a method of treatment comprising identifying a patient with a FRα expressing cancer, followed by administration of the CoStAR cell such as TILs, wherein the subject does not receive exogenous IL-2.
Armstrong et al., in the same field of endeavor, teaches that FRα is expressed by ovarian cancers (Abstract): “…folate receptor-α, which is over-expressed in most epithelial ovarian cancers but largely absent on normal tissue.” Armstrong et al. further teaches that therapies targeting FRα can successfully treat ovarian cancer in humans (Abstract): “…eligible subjects received open-label farletuzumab weekly, single agent or combined with carboplatin (AUC5–6) and taxane (paclitaxel 175 mg/m2 or docetaxel 75 mg/m2), every 21 days for 6 cycles, followed by farletuzumab maintenance until progression” (Discussion): “[i]n our study, overall treatment responses with combination therapy were better than those in other studies of platinum-based combination therapies with 87% of subjects having GCIG response, 81% achieving normal CA125 response, and 75% with RECIST complete or partial response…”
Ikarashi et al., in the same field of endeavor teaches a method of treating subjects with epithelial ovarian cancer comprising adoptive transfer (i.e., “administration”) of tumor infiltrating lymphocytes (i.e., “identifying a subject in need of TIL therapy”; Abstract): “…12 patients with epithelial ovarian cancer who received adoptive transfer of tumor-infiltrating lymphocytes (TILs) after cisplatin containing chemotherapy (TIL group). As a control, 10 patients with epithelial ovarian cancer who did not receive infusions of TIL were also examined in the same fashion…”.
Ikarashi et al. further teaches the method comprises isolating TILs from cancerous tissue from patients, cultured ex vivo and then re-administered to patients with the autologous cancer as adoptive cellular therapy (“Treatment Design” and “Culture and Infusion of TILs” Section). Ikarashi et al. further teaches that the patients were no administered exogenous IL-2 (“Treatment Design” Section): “rIL-2 was used only for TIL cultivation and was not administered to the patients”. Ikarashi et al. teaches that out of 12 patients receiving adoptive TIL therapy, 11 had no evidence of disease (Table 2, supra).
Ikarashi et al. further teaches (Discussion): “[w]ith a median follow-up time of 26.5 months (range, 22-33 months), the 2-year survival rate for the TIL group is 100% by the Kaplan-Meier method, whereas it has been reported that the 2-year survival rate for patients with progressive common epithelial ovarian cancer is 47-63% (34-36). Therefore, the protocol of this study may be effective to improve survival rate.”
Therefore, Ikarashi et al. teaches a method of treating ovarian cancer in a subject comprising administration of TILs, wherein the subject does not receive exogenous IL-2.
It would have been obvious to one with ordinary skill in the art to have modified the invention claimed by App ‘621 in view of Armstrong et al. and Ikarashi et al. to have used the anti-FRα CoStAR expressed on TILs to treat ovarian cancer with a reasonable expectation of success, as App ‘621 claims such CoStARs and cells expressing the fusion polypeptide, Armstrong et al. teaches that FRα is an attractive target for ovarian cancer, and Ikarashi et al. teaches a method of administration of TILs to treat ovarian cancer. One would have been motivated to make this change for the purposes of developing a CoStAR treatment for ovarian cancer.
The combined teachings of App ‘621 in view of Armstrong et al. and Ikarashi et al. teach a method of treating ovarian cancer in a subject with a FRα expressing cancer, comprising identifying a subject with the cancer (who is also in need of TIL therapy) and administering an anti-FRα CoStAR expressing TIL therapy, meeting the limitations of instant claims 1, 82, and 91-94.
Regarding claims 88 and 89, App ‘621 claims CoStARs lacking a signal peptide sequence (claim 36), meeting the claim limitations.
Regarding claim 90, Ikarashi et al. teaches that the patients are administered 1x109 TIL cells in the method of treatment (“Culture and Infusion of TILs” section): “[a]fter 5 weeks of cultivation (3 weeks before freezing and 2 weeks after thawing), the number of cells exceeded 1 x 109. The TILs in 100 ml of sterile saline supplemented with 20 ml of 25% albumin were administered i.v. to patients for 15-30 min at one time. Twelve patients whose number of cells reached 1 x 109 by the injection were selected for further investigation”, and the combined references of App ‘621 in view of Armstrong et al. and Ikarashi et al. teach administration of this number of TILs induced to express the anti-FRα CoStAR, meeting the claim limitations.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘621 in view of Armstrong et al. and Ikarashi et al., especially in absence of evidence to the contrary. This is a provisional double patenting rejection.
Claims 1, 82, 84-86, and 88-94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 36, 38, 40-46, 48, and 51-68 of co-pending Application No. 17/843,480 (App ‘480) in view of Armstrong et al. (supra) and Ikarashi et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘480 claims CoStARs comprising an extracellular binding domain of SEQ ID NO: 4, linked to a TM domain, linked to a CD28 signaling domain, linked to a CD40 signaling domain (claim 1). The specification of App ‘480 is referred to for the full scope of SEQ ID NO: 4, and the Table of Sequences of pg. 67-68 define SEQ ID NO: 4 as the MOV19 anti-FRα scFv. SEQ ID NO: 4 of App ‘480 is 100% identical to the extracellular binding domain of instant SEQ ID NO: 70, which comprises the CDRs of SEQ ID NO: 70 and the VH and VL of SEQ ID NO: 3 and 5, respectively (i.e., the limitations of instant claims 84-86):
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App ‘480 does not claim a method of treatment comprising identifying a patient with a FRα expressing cancer, followed by administration of the CoStAR cell such as TILs, wherein the subject does not receive exogenous IL-2.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘480 in view of view of Armstrong et al. and Ikarashi et al. for the same reasons discussed for App ‘621 supra. This is a provisional double patenting rejection.
Claims 1 and 88-92 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 44-48, 51, 57, 62-70, 72-76, and 78-94 of co-pending Application No. 17/936,102 (App ‘102) in view of Weekes et al. (Mol Cancer Ther. 2016 Mar;15(3):439-47. doi: 10.1158/1535-7163.MCT-15-0693) and Ikarashi et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘102 claims anti-mesothelin (MSLN) CoStARs comprising an extracellular binding domain that binds to MSLN linked to a TM domain, linked to a CD28 signaling domain, and a CD40 signaling domain (claim 44). App ‘102 additionally claims cells expressing the CoStAR (claim 68), including TILs (claim 68). App ‘102 further claims methods of cell therapy (i.e., “treatment”) comprising identifying a subject that has a cancer that expressed MSLN and administering the CoStAR (claim 72).
App ‘102 does not claim a method of treatment comprising identifying a patient with a MSLN expressing cancer such as ovarian cancer, followed by administration of the CoStAR cell such as TILs, wherein the subject does not receive exogenous IL-2.
Weekes et al., in the same field of endeavor, teaches that MSLN is an attractive therapy target to treat ovarian cancer, for example with antibody therapy (Introduction): “…with high frequency of expression in pancreatic and ovarian tumors, and expression limited to slowly dividing normal tissues with mesothelial cell lining (pleural, pericardia!, and peritoneal surfaces), mesothelin is an attractive antigen target for antibody-based therapies coupled to cytotoxic agents.” Weekes et al. further teaches that anti-MSLN therapy, in this instance an anti-MSLN ADC, can successfully treat ovarian cancer (Discussion): “…DMOT4039A demonstrated evidence of antitumor activity with an acceptable safety profile; therefore, therapeutic targeting of mesothelin represents a feasible approach in the treatment of pancreatic and ovarian cancer.
Ikarashi et al., in the same field of endeavor teaches a method of treating subjects with epithelial ovarian cancer comprising adoptive transfer (i.e., “administration”) of tumor infiltrating lymphocytes (i.e., “identifying a subject in need of TIL therapy”; Abstract): “…12 patients with epithelial ovarian cancer who received adoptive transfer of tumor-infiltrating lymphocytes (TILs) after cisplatin containing chemotherapy (TIL group). As a control, 10 patients with epithelial ovarian cancer who did not receive infusions of TIL were also examined in the same fashion…”.
Ikarashi et al. further teaches the method comprises isolating TILs from cancerous tissue from patients, cultured ex vivo and then re-administered to patients with the autologous cancer as adoptive cellular therapy (“Treatment Design” and “Culture and Infusion of TILs” Section). Ikarashi et al. further teaches that the patients were no administered exogenous IL-2 (“Treatment Design” Section): “rIL-2 was used only for TIL cultivation and was not administered to the patients”. Ikarashi et al. teaches that out of 12 patients receiving adoptive TIL therapy, 11 had no evidence of disease (Table 2, supra).
Ikarashi et al. further teaches (Discussion): “[w]ith a median follow-up time of 26.5 months (range, 22-33 months), the 2-year survival rate for the TIL group is 100% by the Kaplan-Meier method, whereas it has been reported that the 2-year survival rate for patients with progressive common epithelial ovarian cancer is 47-63% (34-36). Therefore, the protocol of this study may be effective to improve survival rate.”
Therefore, Ikarashi et al. teaches a method of treating ovarian cancer in a subject comprising administration of TILs, wherein the subject does not receive exogenous IL-2.
It would have been obvious to one with ordinary skill in the art to have modified the invention claimed by App ‘102 in view of Weekes et al. and Ikarashi et al. to have used the anti-MSLN CoStAR expressed on TILs to treat ovarian cancer with a reasonable expectation of success, as App ‘102 claims such anti-MSLN CoStARs and cells expressing the fusion polypeptide, Weekes et al. teaches that MSLN is an attractive target for ovarian cancer, and Ikarashi et al. teaches a method of administration of TILs to treat ovarian cancer. One would have been motivated to make this change for the purposes of developing a CoStAR treatment for ovarian cancer.
The combined teachings of App ‘102 in view of Weekes et al. and Ikarashi et al. teach a method of treating ovarian cancer in a subject with a MSLN expressing cancer, comprising identifying a subject with the cancer (who is also in need of TIL therapy) and administering an anti-MSLN CoStAR expressing TIL therapy, meeting the limitations of instant claims 1, 91, and 92.
Regarding claims 88 and 89, App ‘102 claims CoStARs lacking a signal peptide sequence (claim 44), and containing signal sequences (claims 45 and 46), meeting the claim limitations.
Regarding claim 90, Ikarashi et al. teaches that the patients are administered 1x109 TIL cells in the method of treatment (“Culture and Infusion of TILs” section): “[a]fter 5 weeks of cultivation (3 weeks before freezing and 2 weeks after thawing), the number of cells exceeded 1 x 109. The TILs in 100 ml of sterile saline supplemented with 20 ml of 25% albumin were administered i.v. to patients for 15-30 min at one time. Twelve patients whose number of cells reached 1 x 109 by the injection were selected for further investigation”, and the combined references of App ‘102 in view of Weekes et al. and Ikarashi et al. teach administration of this number of TILs induced to express the anti-MSLN CoStAR, meeting the claim limitations.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘102 in view of Weekes et al. and Ikarashi et al., especially in absence of evidence to the contrary. This is a provisional double patenting rejection.
Claims 1 and 88-92 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-34, 37-39, and 55-58 of co-pending Application No. 18/157,027 (App ‘027) in view of Weekes et al. (supra) and Ikarashi et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘027 claims anti-mesothelin (MSLN) CoStARs comprising an extracellular binding domain that binds to MSLN linked to a TM domain, linked to a CD28 signaling domain, and a CD40 signaling domain (claims 26 and 27). App ‘027 additionally claims cells expressing the CoStAR (claim 37), including TILs (claim 38).
App ‘027 does not claim a method of treatment comprising identifying a patient with a MSLN expressing cancer such as ovarian cancer, followed by administration of the CoStAR cell such as TILs, wherein the subject does not receive exogenous IL-2.
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘027 in view of Weekes et al. and Ikarashi et al. for the same reasons discussed for App ‘102 supra. This is a provisional double patenting rejection.
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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