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 .
Election/Restrictions
Election was made without traverse in the reply filed on 02/09/2026.
Upon reconsideration, the restriction requirement as set forth in the Office action mailed on 12/11/2025, is hereby withdrawn and nonelected groups of invention are hereby rejoined and fully examined for patentability under 37 CFR 1.104. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Status
The claims filed 11/08/2023 have been entered. Claims 1-33 are pending and under examination.
Priority
The application is a 371 application, filed 05/08/2023, of PCT application PCT/US21/58447, filed 11/08/2021, which claims priority benefits from Provisional No. 63110905, filed 11/06/2020. The effective filing date of this application is 11/06/2020, the filing date of the provisional application.
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 - 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.
iii) the size of the ASCII text file in bytes
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.
Claim Objections
Claims 1, 5, 14, 22, and 11 are objected to because of the following informalities:
Claim 1 recites “anti-and/or anti-cancer tumor immunotherapy” (emphasis added), which are not known classes of immunotherapy.
Claims 5, 14, and 22 recite “hydroxysuccinamide” (emphasis added), which is not a known spelling of a known chemical compound.
Claim 11 recites “a second compositions” (emphasis added) which is not grammatically correct.
Appropriate correction is required.
Applicant is advised that should claim 18 be found allowable, claim 33 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Interpretation
In regards to the objection to claim 1 above, for compact prosecution, the claims are being examined as referring to “anti-tumor and/or anti-cancer immunotherapy” where “anti-and/or anti-cancer tumor immunotherapy” is written, consistent with other claims.
In regards to the objection to claims 5, 14, and 22 above, for compact prosecution, the claims are being examined as referring to “hydroxysuccinimide” where “hydroxysuccinamide” is written.
In regards to the objection to claim 11 above, for compact prosecution, the claims are being examined as referring to “a second composition” where “a second compositions” is written.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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.
Claims 1-33 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.
Claims 1, 9-11, and 19 recite compositions and/or conjugates “comprising, consisting essentially of, and consisting of” recited elements. A person of ordinary skill in the art at the time of filing would not be able to resolve what “consisting essentially of” can include and should exclude in order to preserve the essential features of the composition, as the disclosure is unclear on what explicit features are considered the essential features of the composition. Claims 2-8, 12-18, and 20-33 depend on claims 1, 11, or 19 and fail to resolve the indefiniteness of their parent claims. Claims 8, 17, and 25 further recite a gastrin peptide that “comprises, consists essentially of, or consists of” the listed amino acid sequences. A person of ordinary skill in the art at the time of filing would not be able to resolve what “consisting essentially of” can include and should exclude in order to preserve the essential features of the gastrin peptide, as the disclosure is unclear on what explicit features are considered the essential features of the gastrin peptide and how much functional variation from the disclosed four sequences is acceptable. Claim 27 further recite a method wherein the anti-tumor and/or anti-cancer therapies “comprises, consists essentially of, or consists of” administering an immune checkpoint inhibitor. A person of ordinary skill in the art at the time of filing would not be able to resolve what “consisting essentially of” can include and should exclude in order to preserve the essential features of the method, as the disclosure is unclear on what explicit features are considered the essential features of the method. Claims 28-29 depend on claim 27 and fail to resolve this further indefiniteness.
Claims 31-32 recites the limitation "the composition" in reference to parent claim 26, which depends on independent claim 19. However, claim 19 recites a first composition and a second composition. Therefore, it is unclear which composition claims 31-32 is referring to. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Enablement
Claim 1 and its dependent claims 2-8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for enhancing immune checkpoint inhibitors immunotherapy by administering to gastrin-responsive and immune checkpoint inhibitor-responsive cancers a composition comprising of the gastrin immunogen known as PAS, does not reasonably provide enablement for enhancing any “anti-tumor and/or anti-cancer immunotherapy” by administering to any “tumor and/or cancer” a composition of any “gastrin immunogen”. The dependent claims may recite a more specific “anti-tumor and/or anti-cancer immunotherapy” or “tumor and/or cancer” or “gastrin immunogen” but not all in one claim, and thus no dependent claim fully resolves the lack of enablement for the full scope of the claims.
Claims 9-10 and claim 11 and its dependent claims 12-18, 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating gastrin-responsive tumors and/or cancers using a composition comprising of the gastrin immunogen known as PAS and an anti-tumor and/or anti-cancer T cell specific to the target tumor, does not reasonably provide enablement for treating any “tumor and/or cancer” using any “gastrin immunogen” and any “anti-tumor and/or anti-cancer T cell” as claimed. The dependent claims may recite a more specific “tumor and/or cancer” or specific “gastrin immunogen” or specific “anti-tumor and/or anti-cancer T cell”, but not all in one claim, and thus no dependent claim fully resolves the lack of enablement for the full scope of the claims.
Claim 19 and its dependent claims 20-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for sensitizing gastrin-responsive tumors and/or cancers using a composition comprising of the gastrin immunogen known as PAS, does not reasonably provide enablement for sensitizing any “tumor and/or cancer” using any “gastrin immunogen” as claimed. The dependent claims may recite a more specific “tumor and/or cancer” or specific “gastrin immunogen”, but not all in one claim, and thus no dependent claim fully resolves the lack of enablement for the full scope of the claims.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
Pursuant to In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), the following factors are used to determine whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue": (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The analysis is as follows:
(A) The breadth of the claims:
The claims are drawn to enhancing any “anti-tumor and/or anti-cancer immunotherapy” by administering to any “tumor and/or cancer” a composition comprising of any “gastrin immunogen”.
The claims are drawn to enhancing any “anti-tumor and/or anti-cancer immunotherapy” by administering to a gastrointestinal cancer a composition comprising of any “gastrin immunogen”.
The claims are drawn to enhancing any “anti-tumor and/or anti-cancer immunotherapy” by administering to any “tumor and/or cancer” a composition comprising of a gastrin immunogen, comprising of the peptide consisting of SEQ ID NO: 1, 2, 3, or 4, conjugated to an immunogenic carrier.
The claims are drawn to treating any “tumor and/or cancer” using any “gastrin immunogen” and any “anti-tumor and/or anti-cancer T cell”.
The claims are drawn to treating a gastrointestinal tumor and/or cancer using any “gastrin immunogen” and any “anti-tumor and/or anti-cancer T cell”.
The claims are drawn to treating any “tumor and/or cancer” using a composition comprising of a gastrin immunogen, comprising of the peptide consisting of SEQ ID NO: 1, 2, 3, or 4, conjugated to an immunogenic carrier, and any “anti-tumor and/or anti-cancer T cell”.
The claims are drawn to treating any “tumor and/or cancer” using any “gastrin immunogen” and specifically a CAR-T cell that binds to specifically claimed antigens.
The claims are drawn to sensitizing any “tumor and/or cancer” to CAR-T therapy using any “gastrin immunogen”.
The claims are drawn to sensitizing a gastrointestinal tumor and/or cancer to CAR-T therapy using any “gastrin immunogen”.
The claims are drawn to sensitizing any “tumor and/or cancer” to CAR-T therapy using a composition comprising of a gastrin immunogen, comprising of the peptide consisting of SEQ ID NO: 1, 2, 3, or 4, conjugated to an immunogenic carrier.
(B) The nature of the invention:
The nature of the invention is the enhancement of anti-tumor/anti-cancer immunotherapy, the treatment of tumors/cancers, and the sensitizing of tumors/cancers using some combination of anti-tumor/anti-cancer immunotherapy, gastrin immunogen conjugated to an immunogenic carrier, and/or anti-tumor/anti-cancer T cells. Specific species tumors/cancers, anti-tumor/anti-cancer immunotherapy, gastrin immunogen conjugated to an immunogenic carrier, or anti-tumor/anti-cancer T cells are provided in dependent claims, but not together in one claim so that the breadth of the claims remains directed to one or more broad genus of tumors/cancers, anti-tumor/anti-cancer immunotherapy, gastrin immunogen conjugated to an immunogenic carrier, or anti-tumor/anti-cancer T cell.
(C) The state of the prior art:
Regarding the claims drawn to treating a tumor and/or cancer with a gastrin immunogen or specific gastrin immunogens and an anti-tumor/cancer T cell or specific CAR-T cells, the state of the art teaches that there never has been a compound capable of treating cancers generally. In re Application of Hozumi et al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds and classes of compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound or class of compound to be effective against all cancers known and unknown generally. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known.
Even with limiting the cancer/tumor to gastrointestinal or gastrin-responsive cancers/tumors, the scope of the claims regarding the gastrin immunogen would cover all forms of gastrin (e.g. gastrin 14, 17, 34, 71), their full-length amino acid sequences, and all fragments of these sequences. The state of the art, as exemplified by Sutton et al, teaches that gastrin is a growth stimulator of gastrin-responsive tumors/cancers (page 2, paragraph 3; Sutton et al, WO2018/232230A1, published 12/20/2018) and indeed some methods of treating gastrin-responsive cancers/tumors is to inhibit gastrin expression (e.g. Sutton et al, abstract). The prior art, as exemplified by Sutton et al, teaches one gastrin vaccine comprising of SEQ ID NO: 2 as the gastrin immunogen, called PAS. The prior art further teaches SEQ ID NO: 1, 3, and 4 as potential gastrin immunogen, but it is unclear how these variants functionally deviate from SEQ ID NO: 2. Further, these sequences represent only gastrin-17 and fragments thereof. Rehfeld et al teaches that antibodies raised by the PAS vaccine and gastrin immunogens derived from gastrin-17 would only bind gastrin-17, not the major gastrin in circulation, gastrin-34, nor other circulating forms, such as gastrin-71 and gastrin-14, which is problematic if gastrin in the tumor microenvironment is heterogenous and potentially dominated by other forms of gastrin besides gastrin-17 (page 122-123, Rehfeld et al, Gastrin vaccination against gastrointestinal and pancreatic, Scandinavian Journal of Gastroenterology, 2006; 41: 122-123, published 2006). Furthermore, the state of the art teaches that the last 5 amino acids of the C-terminus, called pentagastrin, is common to all bioactive gastrin but this sequence is not included in the PAS vaccine. Rehfeld et al further teaches that if the vaccine-induced antibodies are directed against the C-terminal epitope common for all bioactive gastrins, they might eliminate the growth effects of all gastrin, but it could then also have downstream detrimental effects on physiological pathways that depend on gastrin (page 123, column 1, paragraph 4).
The state of the art is silent on the exact gastrin sequences necessary and sufficient to confer the desired immunogenic effects instead of, or more over, its tumor growth stimulation effects. In other words, gastrin stimulates tumor growth, and it is unclear what portion of gastrin should and can be used as a vaccine besides the sequences instantly claimed and used in the art.
In light of gastrin’s role as a tumor/cancer stimulator, the ability for any gastrin immunogen to sensitize a tumor and/or cancer to CAR-T cell therapy or enhance the effects of other anti-tumor/cancer immunotherapies is similarly unclear without knowing more about the gastrin sequence and the epitope sites that stimulate tumors.
(D) The level of one of ordinary skill:
The relative skill of those in the art is high because enhanced effects of combination therapy of gastrin immunogen and another anti-tumor immunotherapy is not always seen over monotherapies in all cancers. For example, the effects of the combination of the immune checkpoint inhibitor and gastrin immunogen would likely not be enhanced over immune checkpoint inhibitor monotherapy in cancers that do not respond to gastrin.
The relative skill of those in the art is high because of the complex nature of cancer treatment, and the inefficacy of treatments in treating all types of cancer in all patients.
The relative skill of those in the art is high because of the complex nature of modulating the tumor microenvironment so that it is compatible with CAR-T therapy, and the inefficacy of CAR-T cells in all types of cancer, outside of the known treated hematological cancers and promising effects in gastrointestinal tumors. Tumors that do not respond to gastrin immunogens would not reasonably be sensitized to CAR-T therapy, if they were not already sensitized to it.
(E) The level of predictability in the art;
Although there are some known tumors/cancers that respond to gastrin, it does not tell one skilled in the art all the cancers that are or are not responsive to gastrin. Therefore, the search for tumors/cancers that are responsive to a particular therapeutic, such as a gastrin immunogen, is a complex, ongoing, and unpredictable endeavor.
Although there is a known gastrin immunogen used in a cancer vaccine called PAS, the sequence of this one gastrin immunogen, which is the first nine N-terminal amino acids of gastrin-17, this sequence does not tell one skilled in the art what other sequences in the genus of gastrin peptides can be effectively used as a gastrin immunogen in the claimed methods. For example, gastrin-14 is missing some of these amino acids, and gastrin-34 and gastrin-71 comprise of more amino acids than these and more than any of the instantly claimed sequences. In light of gastrin’s role in stimulating tumor and cancer growth and without teachings in the art or disclosure about which sequences should be included or excluded, besides those specifically claimed, one skilled in the art would not be able to predict the structure of the full scope of gastrin immunogens claimed in these methods that recite direct or indirect anti-tumor functions.
In all, the level of predictability regarding the full scope of cancers/tumors and gastrin immunogens is low.
(F) The amount of direction provided by the inventor & (G) The existence of working examples:
The disclosure reduces to practice one composition comprising of PAS, which comprises of SEQ ID NO: 2, as the gastrin immunogen and sometimes one anti-PD-1 antibody (clone RMPI-14) in one disease model of gastric cancer.
Regarding the gastrin immunogen, the disclosure specifically recite SEQ ID NO: 4 as a potential gastrin immunogen, which is the entire amino acid sequence for gastrin 17 and SEQ ID NO: 2 as a potential gastrin immunogen, which is the first nine N-terminal amino acid sequence for gastrin 17. SEQ ID NO: 1 adds one more amino acid to the C-terminus of SEQ ID NO: 2. SEQ ID NO: 3 is the amino acid sequence for gastrin 17 without the last five C-terminal amino acids, known as pentagastrin, which is common to all gastrin forms. SEQ ID NO: 2 is the gastrin immunogen sequence used in the only known gastrin vaccine, PAS (CITE). However, gastrin-14 is missing some of these amino acids common to SEQ ID NO: 1-4, and gastrin-34 and gastrin-71 comprise of more amino acids.
The instant disclosure does not provide any variants of the one known gastrin vaccine.
Regarding the cancers/tumor, the disclosure provides examples with two gastric cancer cell lines.
There are known anti-tumor/cancer immunotherapies and immune checkpoint inhibitors specifically against gastrin-responsive and non-gastrin responsive cancers. There are known CAR-T antigen targets against known gastrin-responsive and non-gastrin responsive cancers. However, it is unclear how these components would work together outside of the disclosed combinations and specifically recited examples to represent the full scope of the claims.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The full scope of the claims would at least require experimentation identifying if a cancer/tumor known and unknown would be sufficiently responsive to gastrin immunogen vaccine so that administration of the gastrin immunogen can enhance any other administered anti-tumor immunotherapy and sensitize the tumor to CAR-T cell therapy. Even within known or identifiable gastrin-responsive cancers, the full scope of the claims would require testing variants of the gastrin immunogen to sufficiently guide sequence design in achieve the desired effects instead of the natural tumor/cancer stimulating effects of gastrin. Even within gastrin-responsive tumors/cancers that are further appropriately responsive to the gastrin immunogen, the full scope of the claims would require identifying whether this particular subset of tumors/cancers are even responsive to known checkpoint inhibitors or CAR-T cell therapies.
Although the task of identifying appropriate cancers/tumors to target, identifying workable variants of the drug, and identifying other immunotherapies that can work in concert, each individually may be routine, albeit complex, experimentation for one skilled in the art, the combination of any of them essentially covers the entire scope of drug discovery and would constitute undue experimentation.
MPEP 2164.01 (a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).”
One case of particular relevance to the question of enablement of a method of treating cancers broadly:
In In re Buting, 57 CCPA 111, 418 F.2d 540, 163 USPQ 689, the claim was drawn to “The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors” using a small genus of compounds. The Court decided that human testing “limited to one compound and two types of cancer” was not “commensurate with the broad scope of utility asserted and claimed”.
In summary, the scope of the claims encompass a broad range of gastrin immunogen variants for use in highly heterogenous cancers/tumors, and even in “gastrin-responsive” cancers/tumors, there is heterogeneity in the type of gastrin present. However, the disclosure and state of the art do not teach any gastrin immunogen variants outside of those derived from gastrin-17 and only in two tumor models of gastric cancer. The level of skill in the art required is high and level of predictability of the art is low regarding determining which sequences to keep or avoid in order to sufficiently raise antibodies against gastrin, and the particular pertinent gastrin forms, without stimulating cancer growth or causing effects counter to treatment. The disclosure and the art does not provide sufficient guidance on this without undue experimentation. Therefore, the invention lack enablement for the full scope of the claims.
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 1-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sutton et al (WO2018/232230A1, published 12/20/2018).
Regarding claim 1, Sutton et al teaches a method for enhancing an anti-tumor and/or anti-cancer immunotherapy, the method comprising administering to a tumor and/or a cancer a composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker, in an amount and via a route sufficient to enhance entry into the tumor and/or cancer of an anti-tumor T cell (Page 71, example 6), whereby an anti-and/or anti-cancer tumor immunotherapy is enhanced (Page 71, example 7). Claims 2-8 depend on claim 1. The teachings of the references regarding claim 1 are incorporated in its entirety for claims 2-8, and discussed further, as is relevant, for each claim below.
Regarding claim 2, Sutton et al teaches wherein the tumor and/or the cancer is a gastrointestinal tumor and/or cancer, optionally a gastrin-dependent gastrointestinal tumor and/or cancer, further optionally a pancreatic tumor and/or cancer, and/or is a gastrin-responsive cancer, optionally a gastrinoma, lung cancer, and/or thyroid cancer (Page 67, Example 1). Of note, the instant specification defines pancreatic cancer as a type of gastrointestinal cancer (Instant specification, page 23, line 13).
Regarding claim 3, Sutton et al teaches wherein the tumor and/or the cancer is a solid tumor and/or cancer of the gastrointestinal tract, optionally a solid tumor and/or cancer of the pancreas (Instant specification, page 23, line 13).
Regarding claim 4, Sutton et al teaches wherein the immunogenic carrier is selected from the group consisting of diphtheria toxoid, tetanus toxoid, keyhole limpet hemocyanin, and bovine serum albumin (Page 33, lines 10-18).
Regarding claim 5, Sutton et al teaches wherein the linker comprises a ɛ-maleimido caproic acid N-hydroxysuccinimide ester.
Regarding claim 6, Sutton et al teaches wherein the linker and the gastrin peptide are separated by an amino acid spacer, optionally wherein the amino acid spacer is between 1 and 10 amino acids in length, further optionally wherein the amino acid spacer is 7 amino acids in length (Page 34, lines 30-33).
Regarding claim 7, Sutton et al teaches wherein the composition further comprises an adjuvant, optionally an oil-based adjuvant (Page 33, lines 15-18).
Regarding claim 8, Sutton et al teaches wherein the gastrin peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of EGPWLEEEEE (SEQ ID NO: 1), EGPWLEEEE (SEQ ID NO: 2), EGPWLEEEEEAY (SEQ ID NO: 3), and EGPWLEEEEEAYGWMDF (SEQ ID NO: 4) (Page 34, line 34 teaches SEQ ID NO: 2; and page 54 teaches SEQ ID NO: 1-4 as options in methods for treating gastrin-associated tumors and/or cancers).
Regarding claims 9-10, Sutton et al teaches a method using a composition comprising of a conjugate comprising a gastrin immunogen and showed that it can enhance anti-tumor and/or anti-cancer T cell entry into a gastrin-associated tumor and/or cancer, thereby teaching the composition of claims 9-10.
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 11-33 are rejected under 35 U.S.C. 103 as being unpatentable over Sutton et al (WO2018/232230A1, published 12/20/2018) in view of Yang et al (Yang, L. et al, Use of immunotherapy in the treatment of gastric cancer, Oncology Letters 18: 5681-5690; published 09/30/2019).
Regarding claim 11, Sutton teaches a method for treating a tumor and/or cancer, optionally a gastrin- associated tumor and/or cancer and/or a gastrin-responsive tumor and/or cancer, in a subject, the method comprising: administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker, in an amount and via a route sufficient to enhance anti-tumor and/or anti-cancer T cell entry into the tumor and/or cancer, whereby the tumor and/or the cancer is treated (Section VI.A. Methods for Treating Gastrin-associated Tumors and/or Cancers; VI. E. Methods for Modulating T Cell Subpopulations in Subjects and Tumors Present Therein; and Example 6).
Regarding claim 19, Sutton teaches a method comprising:(a) administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker.
As is relevant to claims 11 and 19, Sutton et al does not explicitly teach the method further comprises administering to the subject a second composition comprising an anti-tumor and/or anti-cancer T cell, and in particular for claim 19, wherein the anti-tumor and/or anti-cancer T cell comprises a chimeric antigen receptor (CAR) that binds to a tumor-associated and/or cancer-associated antigen present on the tumor and/or the cancer.
As is relevant to claim 19, Sutton et al does not explicitly teach the method for sensitizing a solid tumor and/or cancer in a subject to a chimeric antigen receptor-T (CAR-T) cell therapy, and that the composition is administered in an amount and via a route sufficient to enhance entry of the CAR-T cell into the solid tumor and/or cancer.
Claims 18 and 33 depend on claim 11. The teachings of the references regarding claim 11 are incorporated in its entirety for claim 18 and 33, and discussed further, as is relevant, for each claim below.
As is relevant to claims 18 and 33, Sutton et al does not explicitly teach wherein the CAR binds to an antigen selected from the group consisting of a claudin18.2 antigen, a glypican3 antigen, a mesothelin antigen, a carcinoembryonic antigen (CEA), a prostate stem cell antigen (PSCA), and a CD70 antigen.
However, Yang et al teaches that cancer vaccines, CAR-T cell therapy, and immune checkpoint inhibitors, as well as combination therapy comprising of these immunotherapies, are specifically useful in gastric cancers (Abstract, whole document), as is relevant to claims 11 and 19.
Yang et al further teaches carcinoembryonic antigen (CEA) as a CAR target for gastric cancer in clinical trials (Table I and Page 5686 paragraph 2), as is relevant to claim 18.
Additionally, Sutton et al further teaches that fibrosis in the tumor microenvironment could be implicated in preventing immunotherapy penetration and that the gastrin immunogen conjugated to an immunogenic carrier taught in their method is able to reduce fibrosis in the tumor microenvironment and enhance endogenous anti-tumor T cell penetration into the tumor microenvironment (Page 59, paragraph 2; Examples 5 and 6).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application to combine the gastrin vaccine and the CAR-T therapy taught by Yang et al into the methods of treating gastrointestinal tumors and sensitizing gastrointestinal tumors to anti-tumor T cell penetration taught by Sutton et al, in light of the teachings by Yang et al that gastrin vaccines and CAR-T therapies specifically, and combination therapies comprising of these therapies, have exhibited promising effects in the treatment of gastric cancers (Yang et al, Abstract) and other gastrin-associated cancers of the gastrointestinal tract (Yang et al, Page 5686, column 2, paragraph 2), arriving at the combination of compositions of claim of claims 11 and 19.
Further in light of the teachings of Yang et al that CAR-T therapies have been studied for treatment of solid tumors, specifically gastrointestinal tumors, in combination with the teachings of Sutton et al that their disclosed method of administering a gastrin vaccine to a gastric solid tumor increases endogenous T cell penetration into the tumor, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, that this method would likely also increase penetration of CAR-T cell therapies into the tumor microenvironment. As such, the method, having all the components of the method in claim 19 would also be expected, to sensitize a tumor to CAR-T cell penetration, arriving at all the claim limitations of claim 19.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to specifically choose as the CAR antigen target, a gastrointestinal cancer-related antigen, such as carcinoembryonic antigen (CEA), which Yang et al teaches has already been studied as a successful CAR target in gastrointestinal cancer therapy (Table 1 and Page 5686, paragraphs 2 and 4), arriving at all the limitations of claims 18 and 33.
One skilled in the art, before the effective filing date of the instant application, would be motivated to combine the gastrin vaccine and CAR-T cell therapy since both are taught to be successful in gastrointestinal solid tumors by Yang et al, and Sutton et al teaches the gastrin vaccine enhances tumor penetration by anti-tumor T cell, which would likely extend to CAR-T cells, providing a motivation to combine the two therapies over individual monotherapy, as is relevant to claims 11 and 19. One skilled in the art, before the effective filing date of the instant application, would be motivated to specifically choose CAR’s against known gastrointestinal tumor-related antigens, and specifically one that has already been used successful in CAR-T cell therapies in gastrointestinal cancers, such as the antigen CEA, as is relevant to claims 18 and 33.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success combining the gastrin vaccine and CAR-T cell therapy into methods of treating tumors and sensitizing tumors to CAR-T therapy since both therapies individually have shown efficacy in treating gastrointestinal cancers/tumors, as taught by Yang et al, and there is likely additional benefits to combining them, as evidenced by the results of Sutton et al discussed previously, as is relevant to claims 11 and 19. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success choosing CEA as the antigen that the CAR binds to since it has already been used successful in CAR-T cell therapies in gastrointestinal cancers, as is relevant to claims 18 and 33.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. In this case, the gastrin vaccine and the CAR-T therapies were both taught to be individually efficacious in gastrointestinal cancers, thus combining them for treatment in gastrointestinal cancers is an obvious treatment variant, especially in light of the potential synergistic effects taught in the art. One skilled in the art, before the effective filing date of the instant application, could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately. Although, Sutton et al alludes to potential synergistic effects of the combination therapy, related to the increased penetration of T cells into tumors conferred by gastrin vaccine treatment, amounting to greater effects than each therapy as a monotherapy, each therapy is still performing the same expected function, just at a potentially more effective capacity. One skilled in the art, before the effective filing date of the instant application, would have recognized that the results of the combination were predictable in light of the teachings of increased endogenous anti-tumor T cell penetration into tumors implying the potential to increase penetration of CAR-T cells.
Claims 12-17 depend on claim 11. Claims 20-32 depend on claim 19. The teachings of the references regarding the parent claims are incorporated in its entirety for their dependent, and discussed further, as is relevant, for each claim below.
Regarding claim 12 and 20, Sutton et al further teaches wherein the tumor and/or the cancer is a gastrointestinal tumor and/or cancer, optionally a gastrin-dependent gastrointestinal tumor and/or cancer, further optionally a pancreatic tumor and/or cancer, and/or is a gastrin-responsive cancer, optionally a gastrinoma, lung cancer, and/or thyroid cancer (Page 67, Example 1). Of note, the instant specification defines pancreatic cancer as a type of gastrointestinal cancer (Instant specification, page 23, line 13).
Regarding claim 13 and 21, Sutton et al further teaches wherein the immunogenic carrier is selected from the group consisting of diphtheria toxoid, tetanus toxoid, keyhole limpet hemocyanin, and bovine serum albumin (e.g. Page 33, lines 10-18).
Regarding claim 14 and 22, Sutton et al further teaches wherein the linker comprises a ɛ-maleimido caproic acid N-hydroxysuccinimide ester (e.g. Page 35, lines 1-3).
Regarding claim 15 and 23, Sutton et al further teaches wherein the linker and the gastrin peptide are separated by an amino acid spacer, optionally wherein the amino acid spacer is between 1 and 10 amino acids in length, further optionally wherein the amino acid spacer is 7 amino acids in length (e.g. Page 34, lines 30-33).
Regarding claim 16 and 24, Sutton et al further teaches wherein the composition further comprises an adjuvant, optionally an oil-based adjuvant (Page 33, lines 15-18).
Regarding claim 17 and 25, Sutton et al further teaches wherein the gastrin peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of EGPWLEEEEE (SEQ ID NO: 1), EGPWLEEEE (SEQ ID NO: 2), EGPWLEEEEEAY (SEQ ID NO: 3), and EGPWLEEEEEAYGWMDF (SEQ ID NO: 4) (Page 34, line 34 teaches SEQ ID NO: 2; and page 54 teaches SEQ ID NO: 1-4 as options in methods for treating gastrin-associated tumors and/or cancers).
Regarding claim 26, Sutton et al further teaches methods further comprising administering to the subject one or more additional anti-tumor and/or anti-cancer therapies; and regarding claim 27, specifically that this additional anti-tumor and/or anti-cancer therapies is an immune checkpoint inhibitor (e.g. Figures 2, 6B, 7B, and Examples 2, 5, and 6).
Regarding claim 28, Sutton et al further teaches wherein the immune checkpoint inhibitor inhibits a biological activity of a target polypeptide selected from the group consisting of cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death-1 receptor (PD-1), and programmed cell death 1 receptor ligand (PD-L1) (Page 60-61); and regarding claim 29, specifically the immune checkpoint inhibitors listed in the claim (Page 61, lines 4-6).
Regarding claim 30, Sutton et al further teaches wherein the method reduces and/or inhibits growth of the tumor and/or the cancer in the subject (e.g. Figure 2).
Regarding claim 31, Sutton et al further teaches the administration of the dose claimed (e.g. Page 64, section Study Design; Page 55, lines 19-26).
Claims 32 depend on claim 26, which depends on claim 19. The teachings of the references regarding claims 19 and 26 are incorporated in its entirety for claim 32, and discussed further, as is relevant, below.
Regarding claim 32, Sutton et al does not explicitly teach the one or more additional anti-tumor and/or anti-cancer therapies is administered subsequent to the administration of at least the first dose of the composition.
However, Yang et al teaches that anti-tumor/anti-cancer therapies, specifically immune checkpoint inhibitors, gastrin immunogen conjugated to an immunogenic carrier, and CAR-T cell therapies have individually had varying success in treating gastrointestinal cancers (Abstract, whole document). Sutton et al further teaches that gastrointestinal cancers, such as pancreatic cancer, have dense fibrotic networks that may limit penetration by immunotherapeutics, which could help to explain why checkpoint inhibitors have been characterized by very modest efficacy (Page 59, paragraphs 1-2). Sutton et al specifically teaches that gastrin vaccine and immune checkpoint inhibitors when administered together can provide synergistic effects to make tumors more accessible to immune checkpoint inhibitor drugs by reducing the fibrosis around solid tumors (Page 59, paragraph 2). Even though Sutton et al teaches co-administration and does not explicitly teach subsequent administration of the two components, the teachings of Sutton et al allude to a rationale for delaying administration of immune checkpoint inhibitors until after the tumor microenvironment has been made more permeable to penetration, for example, by administration of one of the other therapies, such as the gastrin vaccine, arriving at all the limitations of claim 32.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that not only is subsequent administration of the therapies an option, it may be desirable over co-administration, as the efficacy of the immune checkpoint inhibitor might not be working to its full potential before the fibrotic network is first reduced by, for example, the gastrin vaccine, especially in light of the teaching by Sutton et al that teaches that gastrin vaccine itself does reduce fibrosis and increases tumor microenvironment permeability to, for example, anti-tumor T cells.
One skilled in the art, before the effective filing date of the instant application, would be motivated to administer the immune checkpoint inhibitor or other anti-tumor therapies after the fibrotic network is reduced first to prevent potential wasteful administration of these drugs during earlier treatment times when they may not be most efficacious. One skilled in the art, before the effective filing date of the instant application, would be motivated to delay administration of the third anti-tumor therapy, such as checkpoint inhibitors, until there is reason to believe they can more effectively penetrate the tumor microenvironment.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success in light of the teachings by Sutton et al that immune checkpoint inhibitors have suffered from only moderate efficiency potentially due to inability to physically penetrate the fibrotic network of the tumor microenvironment and that gastrin vaccine monotherapy itself works to reduce the fibrotic network of the tumor microenvironment.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that if some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, then the combination is obvious. In this case, the motivation to sequentially administer the third therapeutic, such as an immune checkpoint inhibitor, is provided by its known efficacy shortcoming and the potential benefit that could be provided by administering it after another therapeutic had time to increase access into the tumor microenvironment. There is reasonable expectation of success because the first therapeutic, the gastrin vaccine, effectively increases access into the tumor microenvironment, even as a monotherapy, which could reasonably be expected to help increase the efficacy of subsequently administered therapeutics.
Double Patenting
The claims are drawn to enhancing any “anti-tumor and/or anti-cancer immunotherapy” by administering to any “tumor and/or cancer” a composition comprising of any “gastrin immunogen”.
The claims are drawn to treating any “tumor and/or cancer” using any “gastrin immunogen” and any “anti-tumor and/or anti-cancer T cell”.
The claims are drawn to sensitizing any “tumor and/or cancer” to CAR-T therapy using any “gastrin immunogen”.
The USPTO may not institute a derivation proceeding in the absence of a timely filed petition. The U.S. Patent and Trademark Office normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). The applicant should amend or cancel claims such that the reference and the instant application no longer contain claims directed to the same invention.
Nonstatutory 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Application No. 18959355:
Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 8, 11-12, 14, 16-19, and 21 of copending Application No. 18959355 (claims filed 07/07/2025, hereafter referred to as App ‘355). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant disclosure defines a tumor to include all precancerous and cancerous cells, any neoplastic cell growth, whether malignant or benign (Specification, page 20).
Regarding instant claim 1, App ‘355 claims 1-3, 11, 12, and 14 teaches a method of administering a gastrin immunogen conjugated to an immunogenic carrier to prevent initiation or progression of a gastrin-associated tumor/cancer, which inherently will have the intended effects of enhancing other anti-tumor/cancer immunotherapeutics, thereby arriving at all the limitations of instant claim 1.
Instant claims 2-8 depend on instant claim 1. The teachings of the references regarding instant claim 1 are incorporated in its entirety for instant claims 2-8, and discussed further, as is relevant, for each claim below.
Regarding instant claim 2-3, App ‘355 claims 1-3, 11, 12, and 14 further teach a gastrin-associated tumor, and claims 8 and 19 specifically teach pancreatic cancer.
Regarding instant claim 4, App ‘355 claims 3 and 14 further teach the immunogenic carrier options.
Regarding instant claim 5, App ‘355 claims 3 and 14 further teach the linker comprises a ɛ-maleimido caproic acid N-hydroxysuccinimide ester.
Regarding instant claim 6, App ‘355 claims 6 and 17 further teach the amino acid spacer.
Regarding instant claim 7, App ‘355 claim 18 further teaches the adjuvant.
Regarding instant claim 8, App ‘355 claims 2 and 12 further teaches the gastrin peptide sequences.
Regarding instant claims 9-10, App ‘355 teaches a method using a composition comprising of a conjugate comprising a gastrin immunogen, thereby teaching the composition of claims 9-10.
Claims 11-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 8, 11-12, 14, 16-19, and 21 of copending Application No. 18959355 (claims filed 07/07/2025) in view of Sutton et al and further in view of Yang et al. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claims 11-33, App ‘355 claims 1-3, 6, 8, 11-12, 14, 16-19, and 21 teach the limitations regarding a method comprising of administering a gastrin immunogen conjugated to an immunogenic carrier to a gastrin-associated gastrointestinal cancer/tumor.
App ‘355 does not explicitly teach the method also comprises of administering a second composition comprising of an anti-tumor/cancer T cell, or specifically a CAR-T cell targeted against an antigen present on the tumor/cancer.
However, regarding claim 11, Sutton teaches a method for treating a tumor and/or cancer, optionally a gastrin- associated tumor and/or cancer and/or a gastrin-responsive tumor and/or cancer, in a subject, the method comprising: administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker, in an amount and via a route sufficient to enhance anti-tumor and/or anti-cancer T cell entry into the tumor and/or cancer, whereby the tumor and/or the cancer is treated (Section VI.A. Methods for Treating Gastrin-associated Tumors and/or Cancers; VI. E. Methods for Modulating T Cell Subpopulations in Subjects and Tumors Present Therein; and Example 6).
Regarding claim 19, Sutton teaches a method comprising:(a) administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker.
As is relevant to claims 11 and 19, Sutton et al does not explicitly teach the method further comprises administering to the subject a second composition comprising an anti-tumor and/or anti-cancer T cell, and in particular for claim 19, wherein the anti-tumor and/or anti-cancer T cell comprises a chimeric antigen receptor (CAR) that binds to a tumor-associated and/or cancer-associated antigen present on the tumor and/or the cancer.
As is relevant to claim 19, Sutton et al does not explicitly teach the method for sensitizing a solid tumor and/or cancer in a subject to a chimeric antigen receptor-T (CAR-T) cell therapy, and that the composition is administered in an amount and via a route sufficient to enhance entry of the CAR-T cell into the solid tumor and/or cancer.
However, Yang et al teaches that cancer vaccines, CAR-T cell therapy, and immune checkpoint inhibitors, as well as combination therapy comprising of these immunotherapies, are specifically useful in gastric cancers (Abstract, whole document), as is relevant to claims 11 and 19. Additionally, Sutton et al further teaches that fibrosis in the tumor microenvironment could be implicated in preventing immunotherapy penetration and that the gastrin immunogen conjugated to an immunogenic carrier taught in their method is able to reduce fibrosis in the tumor microenvironment and enhance endogenous anti-tumor T cell penetration into the tumor microenvironment (Page 59, paragraph 2; Examples 5 and 6).
Claims 18 and 33 depend on claim 11. The teachings of the references regarding claim 11 are incorporated in its entirety for claim 18 and 33, and discussed further, as is relevant, for each claim below.
Regarding instant claim 18 and 33, App ‘355 does not explicitly teach the CAR’s target antigen.
As is relevant to claims 18 and 33, Sutton et al does not explicitly teach wherein the CAR binds to an antigen selected from the group consisting of a claudin18.2 antigen, a glypican3 antigen, a mesothelin antigen, a carcinoembryonic antigen (CEA), a prostate stem cell antigen (PSCA), and a CD70 antigen.
Yang et al further teaches carcinoembryonic antigen (CEA) as a CAR target for gastric cancer in clinical trials (Table I and Page 5686 paragraph 2), as is relevant to claim 18.
It would have been obvious to one skilled in the art to combine the gastrin vaccine and the CAR-T therapy taught by Yang et al into the methods of treating gastrointestinal tumors and sensitizing gastrointestinal tumors to anti-tumor T cell penetration taught by Sutton et al, in light of the teachings by Yang et al that gastrin vaccines and CAR-T therapies specifically, and combination therapies comprising of these therapies, have exhibited promising effects in the treatment of gastric cancers (Yang et al, Abstract) and other gastrin-associated cancers of the gastrointestinal tract (Yang et al, Page 5686, column 2, paragraph 2), arriving at the combination of compositions of claim of claims 11 and 19.
Further in light of the teachings of Yang et al that CAR-T therapies have been studied for treatment of solid tumors, specifically gastrointestinal tumors, in combination with the teachings of Sutton et al that their disclosed method of administering a gastrin vaccine to a gastric solid tumor increases endogenous T cell penetration into the tumor, it would have been obvious to one skilled in the art that this method would likely also increase penetration of CAR-T cell therapies into the tumor microenvironment. As such, the method, having all the components of the method in claim 19 would also be expected, to sensitize a tumor to CAR-T cell penetration, arriving at all the claim limitations of claim 19.
It would have been obvious to one skilled in the art to specifically choose as the CAR antigen target, a gastrointestinal cancer-related antigen, such as carcinoembryonic antigen (CEA), which Yang et al teaches has already been studied as a successful CAR target in gastrointestinal cancer therapy (Table 1 and Page 5686, paragraphs 2 and 4), arriving at all the limitations of claims 18 and 33.
One skilled in the art would be motivated to combine the gastrin vaccine and CAR-T cell therapy since both are taught to be successful in gastrointestinal solid tumors by Yang et al, and Sutton et al teaches the gastrin vaccine enhances tumor penetration by anti-tumor T cell, which would likely extend to CAR-T cells, providing a motivation to combine the two therapies over individual monotherapy, as is relevant to claims 11 and 19. One skilled in the art would be motivated to specifically choose CAR’s against known gastrointestinal tumor-related antigens, and specifically one that has already been used successful in CAR-T cell therapies in gastrointestinal cancers, such as the antigen CEA, as is relevant to claims 18 and 33.
One skilled in the art would have reasonable expectation of success combining the gastrin vaccine and CAR-T cell therapy into methods of treating tumors and sensitizing tumors to CAR-T therapy since both therapies individually have shown efficacy in treating gastrointestinal cancers/tumors, as taught by Yang et al, and there is likely additional benefits to combining them, as evidenced by the results of Sutton et al discussed previously, as is relevant to claims 11 and 19. One skilled in the art would have reasonable expectation of success choosing CEA as the antigen that the CAR binds to since it has already been used successful in CAR-T cell therapies in gastrointestinal cancers, as is relevant to claims 18 and 33.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. In this case, the gastrin vaccine and the CAR-T therapies were both taught to be individually efficacious in gastrointestinal cancers, thus combining them for treatment in gastrointestinal cancers is an obvious treatment variant, especially in light of the potential synergistic effects taught in the art. One skilled in the art could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately. Although, Sutton et al alludes to potential synergistic effects of the combination therapy, related to the increased penetration of T cells into tumors conferred by gastrin vaccine treatment, amounting to greater effects than each therapy as a monotherapy, each therapy is still performing the same expected function, just at a potentially more effective capacity. One skilled in the art would have recognized that the results of the combination were predictable in light of the teachings of increased endogenous anti-tumor T cell penetration into tumors implying the potential to increase penetration of CAR-T cells.
The teachings to administer the gastrin immunogen conjugated to an immune carrier combined with the rationale and teachings to also administer an anti-tumor/cancer T cell, specifically a CAR-T cell, as taught by App ‘355 claims in view of Sutton et al and further in view of Yang et al, arrives at all the limitations of instant claims 11 and 19 and their dependent claims 12-17, 20-25, 30-31.
Claims 26-29 depend on claim 19. The teachings of the references regarding claim 19 are incorporated in its entirety for claims 26-29, and discussed further, as is relevant, for each claim below.
Regarding instant claims 26-29, App ‘355 does not explicitly teach the additional anti-tumor/anti-cancer therapies, that it could be an immune checkpoint inhibitor, the target polypeptides of these immune checkpoint inhibitors, and the specific immune checkpoint inhibitors by name or designation.
However, regarding claim 26, Sutton et al further teaches methods further comprising administering to the subject one or more additional anti-tumor and/or anti-cancer therapies; and regarding claim 27, specifically that this additional anti-tumor and/or anti-cancer therapies is an immune checkpoint inhibitor (e.g. Figures 2, 6B, 7B, and Examples 2, 5, and 6).
Regarding claim 28, Sutton et al further teaches wherein the immune checkpoint inhibitor inhibits a biological activity of a target polypeptide selected from the group consisting of cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death-1 receptor (PD-1), and programmed cell death 1 receptor ligand (PD-L1) (Page 60-61); and regarding claim 29, specifically the immune checkpoint inhibitors listed in the claim (Page 61, lines 4-6).
These further teachings by Sutton et al, in addition to the teachings by App ‘355 claims in view of Sutton et al and further in view of Yang et al as previously discussed, arrive at all the limitations of instant claims 26-29.
Regarding instant claim 32, App ‘355 and Sutton et al does not explicitly teach the one or more additional anti-tumor and/or anti-cancer therapies is administered subsequent to the administration of at least the first dose of the composition.
However, Yang et al teaches that anti-tumor/anti-cancer therapies, specifically immune checkpoint inhibitors, gastrin immunogen conjugated to an immunogenic carrier, and CAR-T cell therapies have individually had varying success in treating gastrointestinal cancers (Abstract, whole document). Sutton et al further teaches that gastrointestinal cancers, such as pancreatic cancer, have dense fibrotic networks that may limit penetration by immunotherapeutics, which could help to explain why checkpoint inhibitors have been characterized by very modest efficacy (Page 59, paragraphs 1-2). Sutton et al specifically teaches that gastrin vaccine and immune checkpoint inhibitors when administered together can provide synergistic effects to make tumors more accessible to immune checkpoint inhibitor drugs by reducing the fibrosis around solid tumors (Page 59, paragraph 2). Even though Sutton et al teaches co-administration and does not explicitly teach subsequent administration of the two components, the teachings of Sutton et al allude to a rationale for delaying administration of immune checkpoint inhibitors until after the tumor microenvironment has been made more permeable to penetration, for example, by administration of one of the other therapies, such as the gastrin vaccine, arriving at all the limitations of claim 32.
It would have been obvious to one skilled in the art that not only is subsequent administration of the therapies an option, it may be desirable over co-administration, as the efficacy of the immune checkpoint inhibitor might not be working to its full potential before the fibrotic network is first reduced by, for example, the gastrin vaccine, especially in light of the teaching by Sutton et al that teaches that gastrin vaccine itself does reduce fibrosis and increases tumor microenvironment permeability to, for example, anti-tumor T cells.
One skilled in the art would be motivated to administer the immune checkpoint inhibitor or other anti-tumor therapies after the fibrotic network is reduced first to prevent potential wasteful administration of these drugs during earlier treatment times when they may not be most efficacious. One skilled in the art would be motivated to delay administration of the third anti-tumor therapy, such as checkpoint inhibitors, until there is reason to believe they can more effectively penetrate the tumor microenvironment.
One skilled in the art would have reasonable expectation of success in light of the teachings by Sutton et al that immune checkpoint inhibitors have suffered from only moderate efficiency potentially due to inability to physically penetrate the fibrotic network of the tumor microenvironment and that gastrin vaccine monotherapy itself works to reduce the fibrotic network of the tumor microenvironment.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that if some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, then the combination is obvious. In this case, the motivation to sequentially administer the third therapeutic, such as an immune checkpoint inhibitor, is provided by its known efficacy shortcoming and the potential benefit that could be provided by administering it after another therapeutic had time to increase access into the tumor microenvironment. There is reasonable expectation of success because the first therapeutic, the gastrin vaccine, effectively increases access into the tumor microenvironment, even as a monotherapy, which could reasonably be expected to help increase the efficacy of subsequently administered therapeutics.
Application No. 18272329:
Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-22 of copending Application No. 18272329 (claims filed 03/27/2025, hereafter referred to as App ‘329). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant disclosure defines a tumor to include all precancerous and cancerous cells, any neoplastic cell growth, whether malignant or benign (Specification, page 20).
Regarding instant claim 1, App ‘329 claims 1, 11-12, 14 teaches a method of administering a gastrin immunogen conjugated to an immunogenic carrier to prevent initiation or progression of a gastrin-associated tumor/cancer, which inherently will have the intended effects of enhancing other anti-tumor/cancer immunotherapeutics, thereby arriving at all the limitations of instant claim 1.
Instant claims 2-8 depend on instant claim 1. The teachings of the references regarding instant claim 1 are incorporated in its entirety for instant claims 2-8, and discussed further, as is relevant, for each claim below.
Regarding instant claim 2-3, App ‘329 claims 1 and 11 further teach a gastrin-associated tumor or precancerous lesion, and claim 19 specifically teach pancreatic cancer.
Regarding instant claim 4, App ‘329 claims 15 further teach the immunogenic carrier options.
Regarding instant claim 5, App ‘329 claim 16 further teaches the linker comprises a ɛ-maleimido caproic acid N-hydroxysuccinimide ester.
Regarding instant claim 6, App ‘329 claim 17 further teaches the amino acid spacer.
Regarding instant claim 7, App ‘329 claim 18 further teaches the adjuvant.
Regarding instant claim 8, App ‘329 claim 13 further teaches the gastrin peptide sequences.
Regarding instant claims 9-10, App ‘329 teaches a method using a composition comprising of a conjugate comprising a gastrin immunogen, thereby teaching the composition of claims 9-10.
Claims 11-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-22 of copending Application No. 18272329 (claims filed 03/27/2025) in view of Sutton et al and further in view of Yang et al. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claims 11-33, App ‘329 claims 1, 11-22 teach the limitations regarding a method comprising of administering a gastrin immunogen conjugated to an immunogenic carrier to a gastrin-associated gastrointestinal cancer/tumor.
App ‘329 does not explicitly teach the method also comprises of administering a second composition comprising of an anti-tumor/cancer T cell, or specifically a CAR-T cell targeted against an antigen present on the tumor/cancer.
However, regarding claim 11, Sutton teaches a method for treating a tumor and/or cancer, optionally a gastrin- associated tumor and/or cancer and/or a gastrin-responsive tumor and/or cancer, in a subject, the method comprising: administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker, in an amount and via a route sufficient to enhance anti-tumor and/or anti-cancer T cell entry into the tumor and/or cancer, whereby the tumor and/or the cancer is treated (Section VI.A. Methods for Treating Gastrin-associated Tumors and/or Cancers; VI. E. Methods for Modulating T Cell Subpopulations in Subjects and Tumors Present Therein; and Example 6).
Regarding claim 19, Sutton teaches a method comprising:(a) administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker.
As is relevant to claims 11 and 19, Sutton et al does not explicitly teach the method further comprises administering to the subject a second composition comprising an anti-tumor and/or anti-cancer T cell, and in particular for claim 19, wherein the anti-tumor and/or anti-cancer T cell comprises a chimeric antigen receptor (CAR) that binds to a tumor-associated and/or cancer-associated antigen present on the tumor and/or the cancer.
As is relevant to claim 19, Sutton et al does not explicitly teach the method for sensitizing a solid tumor and/or cancer in a subject to a chimeric antigen receptor-T (CAR-T) cell therapy, and that the composition is administered in an amount and via a route sufficient to enhance entry of the CAR-T cell into the solid tumor and/or cancer.
However, Yang et al teaches that cancer vaccines, CAR-T cell therapy, and immune checkpoint inhibitors, as well as combination therapy comprising of these immunotherapies, are specifically useful in gastric cancers (Abstract, whole document), as is relevant to claims 11 and 19. Additionally, Sutton et al further teaches that fibrosis in the tumor microenvironment could be implicated in preventing immunotherapy penetration and that the gastrin immunogen conjugated to an immunogenic carrier taught in their method is able to reduce fibrosis in the tumor microenvironment and enhance endogenous anti-tumor T cell penetration into the tumor microenvironment (Page 59, paragraph 2; Examples 5 and 6).
Claims 18 and 33 depend on claim 11. The teachings of the references regarding claim 11 are incorporated in its entirety for claim 18 and 33, and discussed further, as is relevant, for each claim below.
Regarding instant claim 18 and 33, App ‘329 does not explicitly teach the CAR’s target antigen.
As is relevant to claims 18 and 33, Sutton et al does not explicitly teach wherein the CAR binds to an antigen selected from the group consisting of a claudin18.2 antigen, a glypican3 antigen, a mesothelin antigen, a carcinoembryonic antigen (CEA), a prostate stem cell antigen (PSCA), and a CD70 antigen.
Yang et al further teaches carcinoembryonic antigen (CEA) as a CAR target for gastric cancer in clinical trials (Table I and Page 5686 paragraph 2), as is relevant to claim 18.
It would have been obvious to one skilled in the art to combine the gastrin vaccine and the CAR-T therapy taught by Yang et al into the methods of treating gastrointestinal tumors and sensitizing gastrointestinal tumors to anti-tumor T cell penetration taught by Sutton et al, in light of the teachings by Yang et al that gastrin vaccines and CAR-T therapies specifically, and combination therapies comprising of these therapies, have exhibited promising effects in the treatment of gastric cancers (Yang et al, Abstract) and other gastrin-associated cancers of the gastrointestinal tract (Yang et al, Page 5686, column 2, paragraph 2), arriving at the combination of compositions of claim of claims 11 and 19.
Further in light of the teachings of Yang et al that CAR-T therapies have been studied for treatment of solid tumors, specifically gastrointestinal tumors, in combination with the teachings of Sutton et al that their disclosed method of administering a gastrin vaccine to a gastric solid tumor increases endogenous T cell penetration into the tumor, it would have been obvious to one skilled in the art that this method would likely also increase penetration of CAR-T cell therapies into the tumor microenvironment. As such, the method, having all the components of the method in claim 19 would also be expected, to sensitize a tumor to CAR-T cell penetration, arriving at all the claim limitations of claim 19.
It would have been obvious to One skilled in the art to specifically choose as the CAR antigen target, a gastrointestinal cancer-related antigen, such as carcinoembryonic antigen (CEA), which Yang et al teaches has already been studied as a successful CAR target in gastrointestinal cancer therapy (Table 1 and Page 5686, paragraphs 2 and 4), arriving at all the limitations of claims 18 and 33.
One skilled in the art would be motivated to combine the gastrin vaccine and CAR-T cell therapy since both are taught to be successful in gastrointestinal solid tumors by Yang et al, and Sutton et al teaches the gastrin vaccine enhances tumor penetration by anti-tumor T cell, which would likely extend to CAR-T cells, providing a motivation to combine the two therapies over individual monotherapy, as is relevant to claims 11 and 19. One skilled in the art would be motivated to specifically choose CAR’s against known gastrointestinal tumor-related antigens, and specifically one that has already been used successful in CAR-T cell therapies in gastrointestinal cancers, such as the antigen CEA, as is relevant to claims 18 and 33.
One skilled in the art would have reasonable expectation of success combining the gastrin vaccine and CAR-T cell therapy into methods of treating tumors and sensitizing tumors to CAR-T therapy since both therapies individually have shown efficacy in treating gastrointestinal cancers/tumors, as taught by Yang et al, and there is likely additional benefits to combining them, as evidenced by the results of Sutton et al discussed previously, as is relevant to claims 11 and 19. One skilled in the art would have reasonable expectation of success choosing CEA as the antigen that the CAR binds to since it has already been used successful in CAR-T cell therapies in gastrointestinal cancers, as is relevant to claims 18 and 33.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. In this case, the gastrin vaccine and the CAR-T therapies were both taught to be individually efficacious in gastrointestinal cancers, thus combining them for treatment in gastrointestinal cancers is an obvious treatment variant, especially in light of the potential synergistic effects taught in the art. One skilled in the art could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately. Although, Sutton et al alludes to potential synergistic effects of the combination therapy, related to the increased penetration of T cells into tumors conferred by gastrin vaccine treatment, amounting to greater effects than each therapy as a monotherapy, each therapy is still performing the same expected function, just at a potentially more effective capacity. One skilled in the art would have recognized that the results of the combination were predictable in light of the teachings of increased endogenous anti-tumor T cell penetration into tumors implying the potential to increase penetration of CAR-T cells.
The teachings to administer the gastrin immunogen conjugated to an immune carrier combined with the rationale and teachings to also administer an anti-tumor/cancer T cell, specifically a CAR-T cell, as taught by App ‘329 claims in view of Sutton et al and further in view of Yang et al, arrives at all the limitations of instant claims 11 and 19 and their dependent claims 12-17, 20-25, 30-31.
Claims 26-29 depend on claim 19. The teachings of the references regarding claim 19 are incorporated in its entirety for claims 26-29, and discussed further, as is relevant, for each claim below.
Regarding instant claims 26-29, App ‘329 does not explicitly teach the additional anti-tumor/anti-cancer therapies, that it could be an immune checkpoint inhibitor, the target polypeptides of these immune checkpoint inhibitors, and the specific immune checkpoint inhibitors by name or designation.
However, regarding claim 26, Sutton et al further teaches methods further comprising administering to the subject one or more additional anti-tumor and/or anti-cancer therapies; and regarding claim 27, specifically that this additional anti-tumor and/or anti-cancer therapies is an immune checkpoint inhibitor (e.g. Figures 2, 6B, 7B, and Examples 2, 5, and 6).
Regarding claim 28, Sutton et al further teaches wherein the immune checkpoint inhibitor inhibits a biological activity of a target polypeptide selected from the group consisting of cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death-1 receptor (PD-1), and programmed cell death 1 receptor ligand (PD-L1) (Page 60-61); and regarding claim 29, specifically the immune checkpoint inhibitors listed in the claim (Page 61, lines 4-6).
These further teachings by Sutton et al, in addition to the teachings by App ‘329 claims in view of Sutton et al and further in view of Yang et al as previously discussed, arrive at all the limitations of instant claims 26-29.
Regarding instant claim 32, App ‘329 and Sutton et al does not explicitly teach the one or more additional anti-tumor and/or anti-cancer therapies is administered subsequent to the administration of at least the first dose of the composition.
However, Yang et al teaches that anti-tumor/anti-cancer therapies, specifically immune checkpoint inhibitors, gastrin immunogen conjugated to an immunogenic carrier, and CAR-T cell therapies have individually had varying success in treating gastrointestinal cancers (Abstract, whole document). Sutton et al further teaches that gastrointestinal cancers, such as pancreatic cancer, have dense fibrotic networks that may limit penetration by immunotherapeutics, which could help to explain why checkpoint inhibitors have been characterized by very modest efficacy (Page 59, paragraphs 1-2). Sutton et al specifically teaches that gastrin vaccine and immune checkpoint inhibitors when administered together can provide synergistic effects to make tumors more accessible to immune checkpoint inhibitor drugs by reducing the fibrosis around solid tumors (Page 59, paragraph 2). Even though Sutton et al teaches co-administration and does not explicitly teach subsequent administration of the two components, the teachings of Sutton et al allude to a rationale for delaying administration of immune checkpoint inhibitors until after the tumor microenvironment has been made more permeable to penetration, for example, by administration of one of the other therapies, such as the gastrin vaccine, arriving at all the limitations of claim 32.
It would have been obvious to one skilled in the art that not only is subsequent administration of the therapies an option, it may be desirable over co-administration, as the efficacy of the immune checkpoint inhibitor might not be working to its full potential before the fibrotic network is first reduced by, for example, the gastrin vaccine, especially in light of the teaching by Sutton et al that teaches that gastrin vaccine itself does reduce fibrosis and increases tumor microenvironment permeability to, for example, anti-tumor T cells.
One skilled in the art would be motivated to administer the immune checkpoint inhibitor or other anti-tumor therapies after the fibrotic network is reduced first to prevent potential wasteful administration of these drugs during earlier treatment times when they may not be most efficacious. One skilled in the art would be motivated to delay administration of the third anti-tumor therapy, such as checkpoint inhibitors, until there is reason to believe they can more effectively penetrate the tumor microenvironment.
One skilled in the art would have reasonable expectation of success in light of the teachings by Sutton et al that immune checkpoint inhibitors have suffered from only moderate efficiency potentially due to inability to physically penetrate the fibrotic network of the tumor microenvironment and that gastrin vaccine monotherapy itself works to reduce the fibrotic network of the tumor microenvironment.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that if some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, then the combination is obvious. In this case, the motivation to sequentially administer the third therapeutic, such as an immune checkpoint inhibitor, is provided by its known efficacy shortcoming and the potential benefit that could be provided by administering it after another therapeutic had time to increase access into the tumor microenvironment. There is reasonable expectation of success because the first therapeutic, the gastrin vaccine, effectively increases access into the tumor microenvironment, even as a monotherapy, which could reasonably be expected to help increase the efficacy of subsequently administered therapeutics.
Application No. 18823084:
Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 60-69, 71-73, 76-79, 81-83 of copending Application No. 18823084 (claims filed 04/17/2025, hereafter referred to as App ‘084). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant disclosure defines a tumor to include all precancerous and cancerous cells, any neoplastic cell growth, whether malignant or benign (Specification, page 20).
Regarding instant claim 1, App ‘084 claims 60-64 teaches a method of administering a gastrin immunogen conjugated to an immunogenic carrier to induce and/or enhance a cellular immune response against a gastrin-associated tumor/cancer, which inherently will have the intended effects of enhancing other anti-tumor/cancer immunotherapeutics, thereby arriving at all the limitations of instant claim 1.
Instant claims 2-8 depend on instant claim 1. The teachings of the references regarding instant claim 1 are incorporated in its entirety for instant claims 2-8, and discussed further, as is relevant, for each claim below.
Regarding instant claim 2-3, App ‘084 claims 60-64 further teach a gastrin-associated tumor.
Regarding instant claim 4, App ‘084 claim 64 further teaches the immunogenic carrier options.
Regarding instant claim 5, App ‘084 claim 65 further teaches the linker comprises a ɛ-maleimido caproic acid N-hydroxysuccinimide ester..
Regarding instant claim 6, App ‘084 claim 66 further teaches the amino acid spacer.
Regarding instant claim 7, App ‘084 claim 67 further teaches the adjuvant.
Regarding instant claim 8, App ‘084 claim 63 further teaches the gastrin peptide sequences.
Regarding instant claims 9-10, App ‘084 teaches a method using a composition comprising of a conjugate comprising a gastrin immunogen, thereby teaching the composition of claims 9-10.
Claims 11-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 60-69, 71-73, 76-79, 81-83 of copending Application No. 18823084 (claims filed 04/17/2025) in view of Sutton et al and further in view of Yang et al. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claims 11-33, App ‘084 claims 60-69, 71-73, 76-79, 81-83 teach the limitations regarding a method comprising of administering a gastrin immunogen conjugated to an immunogenic carrier to a gastrin-associated gastrointestinal cancer/tumor.
App ‘084 does not explicitly teach the method also comprises of administering a second composition comprising of an anti-tumor/cancer T cell, or specifically a CAR-T cell targeted against an antigen present on the tumor/cancer.
However, regarding claim 11, Sutton teaches a method for treating a tumor and/or cancer, optionally a gastrin- associated tumor and/or cancer and/or a gastrin-responsive tumor and/or cancer, in a subject, the method comprising: administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker, in an amount and via a route sufficient to enhance anti-tumor and/or anti-cancer T cell entry into the tumor and/or cancer, whereby the tumor and/or the cancer is treated (Section VI.A. Methods for Treating Gastrin-associated Tumors and/or Cancers; VI. E. Methods for Modulating T Cell Subpopulations in Subjects and Tumors Present Therein; and Example 6).
Regarding claim 19, Sutton teaches a method comprising:(a) administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker.
As is relevant to claims 11 and 19, Sutton et al does not explicitly teach the method further comprises administering to the subject a second composition comprising an anti-tumor and/or anti-cancer T cell, and in particular for claim 19, wherein the anti-tumor and/or anti-cancer T cell comprises a chimeric antigen receptor (CAR) that binds to a tumor-associated and/or cancer-associated antigen present on the tumor and/or the cancer.
As is relevant to claim 19, Sutton et al does not explicitly teach the method for sensitizing a solid tumor and/or cancer in a subject to a chimeric antigen receptor-T (CAR-T) cell therapy, and that the composition is administered in an amount and via a route sufficient to enhance entry of the CAR-T cell into the solid tumor and/or cancer.
However, Yang et al teaches that cancer vaccines, CAR-T cell therapy, and immune checkpoint inhibitors, as well as combination therapy comprising of these immunotherapies, are specifically useful in gastric cancers (Abstract, whole document), as is relevant to claims 11 and 19. Additionally, Sutton et al further teaches that fibrosis in the tumor microenvironment could be implicated in preventing immunotherapy penetration and that the gastrin immunogen conjugated to an immunogenic carrier taught in their method is able to reduce fibrosis in the tumor microenvironment and enhance endogenous anti-tumor T cell penetration into the tumor microenvironment (Page 59, paragraph 2; Examples 5 and 6).
Claims 18 and 33 depend on claim 11. The teachings of the references regarding claim 11 are incorporated in its entirety for claim 18 and 33, and discussed further, as is relevant, for each claim below.
Regarding instant claim 18 and 33, App ‘084 does not explicitly teach the CAR’s target antigen.
As is relevant to claims 18 and 33, Sutton et al does not explicitly teach wherein the CAR binds to an antigen selected from the group consisting of a claudin18.2 antigen, a glypican3 antigen, a mesothelin antigen, a carcinoembryonic antigen (CEA), a prostate stem cell antigen (PSCA), and a CD70 antigen.
Yang et al further teaches carcinoembryonic antigen (CEA) as a CAR target for gastric cancer in clinical trials (Table I and Page 5686 paragraph 2), as is relevant to claim 18.
It would have been obvious to one skilled in the art to combine the gastrin vaccine and the CAR-T therapy taught by Yang et al into the methods of treating gastrointestinal tumors and sensitizing gastrointestinal tumors to anti-tumor T cell penetration taught by Sutton et al, in light of the teachings by Yang et al that gastrin vaccines and CAR-T therapies specifically, and combination therapies comprising of these therapies, have exhibited promising effects in the treatment of gastric cancers (Yang et al, Abstract) and other gastrin-associated cancers of the gastrointestinal tract (Yang et al, Page 5686, column 2, paragraph 2), arriving at the combination of compositions of claim of claims 11 and 19.
Further in light of the teachings of Yang et al that CAR-T therapies have been studied for treatment of solid tumors, specifically gastrointestinal tumors, in combination with the teachings of Sutton et al that their disclosed method of administering a gastrin vaccine to a gastric solid tumor increases endogenous T cell penetration into the tumor, it would have been obvious to one skilled in the art that this method would likely also increase penetration of CAR-T cell therapies into the tumor microenvironment. As such, the method, having all the components of the method in claim 19 would also be expected, to sensitize a tumor to CAR-T cell penetration, arriving at all the claim limitations of claim 19.
It would have been obvious to one skilled in the art to specifically choose as the CAR antigen target, a gastrointestinal cancer-related antigen, such as carcinoembryonic antigen (CEA), which Yang et al teaches has already been studied as a successful CAR target in gastrointestinal cancer therapy (Table 1 and Page 5686, paragraphs 2 and 4), arriving at all the limitations of claims 18 and 33.
One skilled in the art would be motivated to combine the gastrin vaccine and CAR-T cell therapy since both are taught to be successful in gastrointestinal solid tumors by Yang et al, and Sutton et al teaches the gastrin vaccine enhances tumor penetration by anti-tumor T cell, which would likely extend to CAR-T cells, providing a motivation to combine the two therapies over individual monotherapy, as is relevant to claims 11 and 19. One skilled in the art would be motivated to specifically choose CAR’s against known gastrointestinal tumor-related antigens, and specifically one that has already been used successful in CAR-T cell therapies in gastrointestinal cancers, such as the antigen CEA, as is relevant to claims 18 and 33.
One skilled in the art would have reasonable expectation of success combining the gastrin vaccine and CAR-T cell therapy into methods of treating tumors and sensitizing tumors to CAR-T therapy since both therapies individually have shown efficacy in treating gastrointestinal cancers/tumors, as taught by Yang et al, and there is likely additional benefits to combining them, as evidenced by the results of Sutton et al discussed previously, as is relevant to claims 11 and 19. One skilled in the art would have reasonable expectation of success choosing CEA as the antigen that the CAR binds to since it has already been used successful in CAR-T cell therapies in gastrointestinal cancers, as is relevant to claims 18 and 33.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. In this case, the gastrin vaccine and the CAR-T therapies were both taught to be individually efficacious in gastrointestinal cancers, thus combining them for treatment in gastrointestinal cancers is an obvious treatment variant, especially in light of the potential synergistic effects taught in the art. One skilled in the art could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately. Although, Sutton et al alludes to potential synergistic effects of the combination therapy, related to the increased penetration of T cells into tumors conferred by gastrin vaccine treatment, amounting to greater effects than each therapy as a monotherapy, each therapy is still performing the same expected function, just at a potentially more effective capacity. One skilled in the art would have recognized that the results of the combination were predictable in light of the teachings of increased endogenous anti-tumor T cell penetration into tumors implying the potential to increase penetration of CAR-T cells.
The teachings to administer the gastrin immunogen conjugated to an immune carrier combined with the rationale and teachings to also administer an anti-tumor/cancer T cell, specifically a CAR-T cell, as taught by App ‘084 claims in view of Sutton et al and further in view of Yang et al, arrives at all the limitations of instant claims 11 and 19 and their dependent claims 12-17, 20-25, 30-31.
Claims 26-29 depend on claim 19. The teachings of the references regarding claim 19 are incorporated in its entirety for claims 26-29, and discussed further, as is relevant, for each claim below.
Regarding instant claims 26-29, App ‘084 claims 78-79 further teach the additional anti-tumor/anti-cancer therapies, such as an inducer for cellular immune response against the gastrin-associated tumor/cancer could be an immune checkpoint inhibitor, the target polypeptides of these immune checkpoint inhibitors, and the specific immune checkpoint inhibitors by name or designation.
Regarding instant claim 32, App ‘084 and Sutton et al does not explicitly teach the one or more additional anti-tumor and/or anti-cancer therapies is administered subsequent to the administration of at least the first dose of the composition.
However, Yang et al teaches that anti-tumor/anti-cancer therapies, specifically immune checkpoint inhibitors, gastrin immunogen conjugated to an immunogenic carrier, and CAR-T cell therapies have individually had varying success in treating gastrointestinal cancers (Abstract, whole document). Sutton et al further teaches that gastrointestinal cancers, such as pancreatic cancer, have dense fibrotic networks that may limit penetration by immunotherapeutics, which could help to explain why checkpoint inhibitors have been characterized by very modest efficacy (Page 59, paragraphs 1-2). Sutton et al specifically teaches that gastrin vaccine and immune checkpoint inhibitors when administered together can provide synergistic effects to make tumors more accessible to immune checkpoint inhibitor drugs by reducing the fibrosis around solid tumors (Page 59, paragraph 2). Even though Sutton et al teaches co-administration and does not explicitly teach subsequent administration of the two components, the teachings of Sutton et al allude to a rationale for delaying administration of immune checkpoint inhibitors until after the tumor microenvironment has been made more permeable to penetration, for example, by administration of one of the other therapies, such as the gastrin vaccine, arriving at all the limitations of claim 32.
It would have been obvious to One skilled in the art that not only is subsequent administration of the therapies an option, it may be desirable over co-administration, as the efficacy of the immune checkpoint inhibitor might not be working to its full potential before the fibrotic network is first reduced by, for example, the gastrin vaccine, especially in light of the teaching by Sutton et al that teaches that gastrin vaccine itself does reduce fibrosis and increases tumor microenvironment permeability to, for example, anti-tumor T cells.
One skilled in the art would be motivated to administer the immune checkpoint inhibitor or other anti-tumor therapies after the fibrotic network is reduced first to prevent potential wasteful administration of these drugs during earlier treatment times when they may not be most efficacious. One skilled in the art would be motivated to delay administration of the third anti-tumor therapy, such as checkpoint inhibitors, until there is reason to believe they can more effectively penetrate the tumor microenvironment.
One skilled in the art would have reasonable expectation of success in light of the teachings by Sutton et al that immune checkpoint inhibitors have suffered from only moderate efficiency potentially due to inability to physically penetrate the fibrotic network of the tumor microenvironment and that gastrin vaccine monotherapy itself works to reduce the fibrotic network of the tumor microenvironment.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that if some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, then the combination is obvious. In this case, the motivation to sequentially administer the third therapeutic, such as an immune checkpoint inhibitor, is provided by its known efficacy shortcoming and the potential benefit that could be provided by administering it after another therapeutic had time to increase access into the tumor microenvironment. There is reasonable expectation of success because the first therapeutic, the gastrin vaccine, effectively increases access into the tumor microenvironment, even as a monotherapy, which could reasonably be expected to help increase the efficacy of subsequently administered therapeutics.
Patent US12150978B2:
Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. US12150978B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant disclosure defines a tumor to include all precancerous and cancerous cells, any neoplastic cell growth, whether malignant or benign (Specification, page 20).
Regarding instant claim 1, Pat ‘978 claims 1-2, 9-10, 16 and 19 teach a method of administering a gastrin immunogen conjugated to an immunogenic carrier to prevent initiation or development of a gastrin-associated tumor/cancer or tumor/cancer-associated fibrosis, which inherently will have the intended effects of enhancing other anti-tumor/cancer immunotherapeutics, thereby arriving at all the limitations of instant claim 1.
Instant claims 2-8 depend on instant claim 1. The teachings of the references regarding instant claim 1 are incorporated in its entirety for instant claims 2-8, and discussed further, as is relevant, for each claim below.
Regarding instant claim 2-3, Pat ‘978 claims 1, 9, 16 further teach a gastrin-associated tumor or neoplasia, and specifically pancreatic cancer/tumor.
Regarding instant claim 4, Pat ‘978 claims 3, 11, 21 further teach the immunogenic carrier options.
Regarding instant claim 5, Pat ‘978 claims 4, 12, 23 further teach the linker comprises a ɛ-maleimido caproic acid N-hydroxysuccinimide ester.
Regarding instant claim 6, Pat ‘978 claims 5, 13, 23 further teach the amino acid spacer.
Regarding instant claim 7, Pat ‘978 claim 6, 14, 25 further teaches the adjuvant.
Regarding instant claim 8, Pat ‘978 claims 1, 9, 20 further teaches the gastrin peptide sequences.
Regarding instant claims 9-10, App ‘978 teaches a method using a composition comprising of a conjugate comprising a gastrin immunogen, thereby teaching the composition of claims 9-10.
Claims 11-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. US12150978B2 in view of Sutton et al and further in view of Yang et al.
Regarding instant claims 11-33, Pat ‘978 claims 1-26 teach the limitations regarding a method comprising of administering a gastrin immunogen conjugated to an immunogenic carrier to a gastrin-associated gastrointestinal cancer/tumor.
Pat ‘978 does not explicitly teach the method also comprises of administering a second composition comprising of an anti-tumor/cancer T cell, or specifically a CAR-T cell targeted against an antigen present on the tumor/cancer.
However, regarding claim 11, Sutton teaches a method for treating a tumor and/or cancer, optionally a gastrin- associated tumor and/or cancer and/or a gastrin-responsive tumor and/or cancer, in a subject, the method comprising: administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker, in an amount and via a route sufficient to enhance anti-tumor and/or anti-cancer T cell entry into the tumor and/or cancer, whereby the tumor and/or the cancer is treated (Section VI.A. Methods for Treating Gastrin-associated Tumors and/or Cancers; VI. E. Methods for Modulating T Cell Subpopulations in Subjects and Tumors Present Therein; and Example 6).
Regarding claim 19, Sutton teaches a method comprising:(a) administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker.
As is relevant to claims 11 and 19, Sutton et al does not explicitly teach the method further comprises administering to the subject a second composition comprising an anti-tumor and/or anti-cancer T cell, and in particular for claim 19, wherein the anti-tumor and/or anti-cancer T cell comprises a chimeric antigen receptor (CAR) that binds to a tumor-associated and/or cancer-associated antigen present on the tumor and/or the cancer.
As is relevant to claim 19, Sutton et al does not explicitly teach the method for sensitizing a solid tumor and/or cancer in a subject to a chimeric antigen receptor-T (CAR-T) cell therapy, and that the composition is administered in an amount and via a route sufficient to enhance entry of the CAR-T cell into the solid tumor and/or cancer.
However, Yang et al teaches that cancer vaccines, CAR-T cell therapy, and immune checkpoint inhibitors, as well as combination therapy comprising of these immunotherapies, are specifically useful in gastric cancers (Abstract, whole document), as is relevant to claims 11 and 19. Additionally, Sutton et al further teaches that fibrosis in the tumor microenvironment could be implicated in preventing immunotherapy penetration and that the gastrin immunogen conjugated to an immunogenic carrier taught in their method is able to reduce fibrosis in the tumor microenvironment and enhance endogenous anti-tumor T cell penetration into the tumor microenvironment (Page 59, paragraph 2; Examples 5 and 6).
Claims 18 and 33 depend on claim 11. The teachings of the references regarding claim 11 are incorporated in its entirety for claim 18 and 33, and discussed further, as is relevant, for each claim below.
Regarding instant claim 18 and 33, Pat ‘978 does not explicitly teach the CAR’s target antigen.
As is relevant to claims 18 and 33, Sutton et al does not explicitly teach wherein the CAR binds to an antigen selected from the group consisting of a claudin18.2 antigen, a glypican3 antigen, a mesothelin antigen, a carcinoembryonic antigen (CEA), a prostate stem cell antigen (PSCA), and a CD70 antigen.
Yang et al further teaches carcinoembryonic antigen (CEA) as a CAR target for gastric cancer in clinical trials (Table I and Page 5686 paragraph 2), as is relevant to claim 18.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application to combine the gastrin vaccine and the CAR-T therapy taught by Yang et al into the methods of treating gastrointestinal tumors and sensitizing gastrointestinal tumors to anti-tumor T cell penetration taught by Sutton et al, in light of the teachings by Yang et al that gastrin vaccines and CAR-T therapies specifically, and combination therapies comprising of these therapies, have exhibited promising effects in the treatment of gastric cancers (Yang et al, Abstract) and other gastrin-associated cancers of the gastrointestinal tract (Yang et al, Page 5686, column 2, paragraph 2), arriving at the combination of compositions of claim of claims 11 and 19.
Further in light of the teachings of Yang et al that CAR-T therapies have been studied for treatment of solid tumors, specifically gastrointestinal tumors, in combination with the teachings of Sutton et al that their disclosed method of administering a gastrin vaccine to a gastric solid tumor increases endogenous T cell penetration into the tumor, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, that this method would likely also increase penetration of CAR-T cell therapies into the tumor microenvironment. As such, the method, having all the components of the method in claim 19 would also be expected, to sensitize a tumor to CAR-T cell penetration, arriving at all the claim limitations of claim 19.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to specifically choose as the CAR antigen target, a gastrointestinal cancer-related antigen, such as carcinoembryonic antigen (CEA), which Yang et al teaches has already been studied as a successful CAR target in gastrointestinal cancer therapy (Table 1 and Page 5686, paragraphs 2 and 4), arriving at all the limitations of claims 18 and 33.
One skilled in the art, before the effective filing date of the instant application, would be motivated to combine the gastrin vaccine and CAR-T cell therapy since both are taught to be successful in gastrointestinal solid tumors by Yang et al, and Sutton et al teaches the gastrin vaccine enhances tumor penetration by anti-tumor T cell, which would likely extend to CAR-T cells, providing a motivation to combine the two therapies over individual monotherapy, as is relevant to claims 11 and 19. One skilled in the art, before the effective filing date of the instant application, would be motivated to specifically choose CAR’s against known gastrointestinal tumor-related antigens, and specifically one that has already been used successful in CAR-T cell therapies in gastrointestinal cancers, such as the antigen CEA, as is relevant to claims 18 and 33.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success combining the gastrin vaccine and CAR-T cell therapy into methods of treating tumors and sensitizing tumors to CAR-T therapy since both therapies individually have shown efficacy in treating gastrointestinal cancers/tumors, as taught by Yang et al, and there is likely additional benefits to combining them, as evidenced by the results of Sutton et al discussed previously, as is relevant to claims 11 and 19. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success choosing CEA as the antigen that the CAR binds to since it has already been used successful in CAR-T cell therapies in gastrointestinal cancers, as is relevant to claims 18 and 33.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. In this case, the gastrin vaccine and the CAR-T therapies were both taught to be individually efficacious in gastrointestinal cancers, thus combining them for treatment in gastrointestinal cancers is an obvious treatment variant, especially in light of the potential synergistic effects taught in the art. One skilled in the art, before the effective filing date of the instant application, could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately. Although, Sutton et al alludes to potential synergistic effects of the combination therapy, related to the increased penetration of T cells into tumors conferred by gastrin vaccine treatment, amounting to greater effects than each therapy as a monotherapy, each therapy is still performing the same expected function, just at a potentially more effective capacity. One skilled in the art, before the effective filing date of the instant application, would have recognized that the results of the combination were predictable in light of the teachings of increased endogenous anti-tumor T cell penetration into tumors implying the potential to increase penetration of CAR-T cells.
The teachings to administer the gastrin immunogen conjugated to an immune carrier combined with the rationale and teachings to also administer an anti-tumor/cancer T cell, specifically a CAR-T cell, as taught by Pat ‘978 claims in view of Sutton et al and further in view of Yang et al, arrives at all the limitations of instant claims 11 and 19 and their dependent claims 12-17, 20-25, 30-31.
Claims 26-29 depend on claim 19. The teachings of the references regarding claim 19 are incorporated in its entirety for claims 26-29, and discussed further, as is relevant, for each claim below.
Regarding instant claims 26-29, Pat ‘978 does not explicitly teach the additional anti-tumor/anti-cancer therapies, that it could be an immune checkpoint inhibitor, the target polypeptides of these immune checkpoint inhibitors, and the specific immune checkpoint inhibitors by name or designation.
However, regarding claim 26, Sutton et al further teaches methods further comprising administering to the subject one or more additional anti-tumor and/or anti-cancer therapies; and regarding claim 27, specifically that this additional anti-tumor and/or anti-cancer therapies is an immune checkpoint inhibitor (e.g. Figures 2, 6B, 7B, and Examples 2, 5, and 6).
Regarding claim 28, Sutton et al further teaches wherein the immune checkpoint inhibitor inhibits a biological activity of a target polypeptide selected from the group consisting of cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death-1 receptor (PD-1), and programmed cell death 1 receptor ligand (PD-L1) (Page 60-61); and regarding claim 29, specifically the immune checkpoint inhibitors listed in the claim (Page 61, lines 4-6).
These further teachings by Sutton et al, in addition to the teachings by Pat ‘978 claims in view of Sutton et al and further in view of Yang et al as previously discussed, arrive at all the limitations of instant claims 26-29.
Regarding instant claim 32, Pat ‘978 and Sutton et al does not explicitly teach the one or more additional anti-tumor and/or anti-cancer therapies is administered subsequent to the administration of at least the first dose of the composition.
However, Yang et al teaches that anti-tumor/anti-cancer therapies, specifically immune checkpoint inhibitors, gastrin immunogen conjugated to an immunogenic carrier, and CAR-T cell therapies have individually had varying success in treating gastrointestinal cancers (Abstract, whole document). Sutton et al further teaches that gastrointestinal cancers, such as pancreatic cancer, have dense fibrotic networks that may limit penetration by immunotherapeutics, which could help to explain why checkpoint inhibitors have been characterized by very modest efficacy (Page 59, paragraphs 1-2). Sutton et al specifically teaches that gastrin vaccine and immune checkpoint inhibitors when administered together can provide synergistic effects to make tumors more accessible to immune checkpoint inhibitor drugs by reducing the fibrosis around solid tumors (Page 59, paragraph 2). Even though Sutton et al teaches co-administration and does not explicitly teach subsequent administration of the two components, the teachings of Sutton et al allude to a rationale for delaying administration of immune checkpoint inhibitors until after the tumor microenvironment has been made more permeable to penetration, for example, by administration of one of the other therapies, such as the gastrin vaccine, arriving at all the limitations of claim 32.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that not only is subsequent administration of the therapies an option, it may be desirable over co-administration, as the efficacy of the immune checkpoint inhibitor might not be working to its full potential before the fibrotic network is first reduced by, for example, the gastrin vaccine, especially in light of the teaching by Sutton et al that teaches that gastrin vaccine itself does reduce fibrosis and increases tumor microenvironment permeability to, for example, anti-tumor T cells.
One skilled in the art, before the effective filing date of the instant application, would be motivated to administer the immune checkpoint inhibitor or other anti-tumor therapies after the fibrotic network is reduced first to prevent potential wasteful administration of these drugs during earlier treatment times when they may not be most efficacious. One skilled in the art, before the effective filing date of the instant application, would be motivated to delay administration of the third anti-tumor therapy, such as checkpoint inhibitors, until there is reason to believe they can more effectively penetrate the tumor microenvironment.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success in light of the teachings by Sutton et al that immune checkpoint inhibitors have suffered from only moderate efficiency potentially due to inability to physically penetrate the fibrotic network of the tumor microenvironment and that gastrin vaccine monotherapy itself works to reduce the fibrotic network of the tumor microenvironment.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that if some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, then the combination is obvious. In this case, the motivation to sequentially administer the third therapeutic, such as an immune checkpoint inhibitor, is provided by its known efficacy shortcoming and the potential benefit that could be provided by administering it after another therapeutic had time to increase access into the tumor microenvironment. There is reasonable expectation of success because the first therapeutic, the gastrin vaccine, effectively increases access into the tumor microenvironment, even as a monotherapy, which could reasonably be expected to help increase the efficacy of subsequently administered therapeutics.
Patent US11583576B2:
Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US11583576B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant disclosure defines a tumor to include all precancerous and cancerous cells, any neoplastic cell growth, whether malignant or benign (Specification, page 20).
Regarding instant claim 1, Pat ‘576 claims 1 teach a method of administering a gastrin immunogen conjugated to an immunogenic carrier to treat/prevent/inhibit of a gastrin-associated tumor/cancer, which inherently will have the intended effects of enhancing other anti-tumor/cancer immunotherapeutics, thereby arriving at all the limitations of instant claim 1.
Instant claims 2-8 depend on instant claim 1. The teachings of the references regarding instant claim 1 are incorporated in its entirety for instant claims 2-8, and discussed further, as is relevant, for each claim below.
Regarding instant claim 2-3, Pat ‘576 claims 1, 9 further teach a gastrin-associated tumor/cancer, and specifically pancreatic cancer/tumor.
Regarding instant claim 4, Pat ‘576 claim 2 further teaches the immunogenic carrier options.
Regarding instant claim 5, Pat ‘576 claim 3 further teaches the linker comprises a ɛ-maleimido caproic acid N-hydroxysuccinimide ester.
Regarding instant claim 6, Pat ‘576 claim 4 further teaches the amino acid spacer.
Regarding instant claim 7, Pat ‘576 claim 5 further teaches the adjuvant.
Regarding instant claim 8, Pat ‘576 claim 1 further teaches the gastrin peptide sequences.
Regarding instant claims 9-10, App ‘576 teaches a method using a composition comprising of a conjugate comprising a gastrin immunogen, thereby teaching the composition of claims 9-10.
Claims 11-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US11583576B2 in view of Sutton et al and further in view of Yang et al.
Regarding instant claims 11-33, Pat ‘576 claims 1-11 teach the limitations regarding a method comprising of administering a gastrin immunogen conjugated to an immunogenic carrier to a gastrin-associated gastrointestinal cancer/tumor.
Pat ‘576 does not explicitly teach the method also comprises of administering a second composition comprising of an anti-tumor/cancer T cell, or specifically a CAR-T cell targeted against an antigen present on the tumor/cancer.
However, regarding claim 11, Sutton teaches a method for treating a tumor and/or cancer, optionally a gastrin- associated tumor and/or cancer and/or a gastrin-responsive tumor and/or cancer, in a subject, the method comprising: administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker, in an amount and via a route sufficient to enhance anti-tumor and/or anti-cancer T cell entry into the tumor and/or cancer, whereby the tumor and/or the cancer is treated (Section VI.A. Methods for Treating Gastrin-associated Tumors and/or Cancers; VI. E. Methods for Modulating T Cell Subpopulations in Subjects and Tumors Present Therein; and Example 6).
Regarding claim 19, Sutton teaches a method comprising:(a) administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker.
As is relevant to claims 11 and 19, Sutton et al does not explicitly teach the method further comprises administering to the subject a second composition comprising an anti-tumor and/or anti-cancer T cell, and in particular for claim 19, wherein the anti-tumor and/or anti-cancer T cell comprises a chimeric antigen receptor (CAR) that binds to a tumor-associated and/or cancer-associated antigen present on the tumor and/or the cancer.
As is relevant to claim 19, Sutton et al does not explicitly teach the method for sensitizing a solid tumor and/or cancer in a subject to a chimeric antigen receptor-T (CAR-T) cell therapy, and that the composition is administered in an amount and via a route sufficient to enhance entry of the CAR-T cell into the solid tumor and/or cancer.
However, Yang et al teaches that cancer vaccines, CAR-T cell therapy, and immune checkpoint inhibitors, as well as combination therapy comprising of these immunotherapies, are specifically useful in gastric cancers (Abstract, whole document), as is relevant to claims 11 and 19. Additionally, Sutton et al further teaches that fibrosis in the tumor microenvironment could be implicated in preventing immunotherapy penetration and that the gastrin immunogen conjugated to an immunogenic carrier taught in their method is able to reduce fibrosis in the tumor microenvironment and enhance endogenous anti-tumor T cell penetration into the tumor microenvironment (Page 59, paragraph 2; Examples 5 and 6).
Claims 18 and 33 depend on claim 11. The teachings of the references regarding claim 11 are incorporated in its entirety for claim 18 and 33, and discussed further, as is relevant, for each claim below.
Regarding instant claim 18 and 33, Pat ‘576 does not explicitly teach the CAR’s target antigen.
As is relevant to claims 18 and 33, Sutton et al does not explicitly teach wherein the CAR binds to an antigen selected from the group consisting of a claudin18.2 antigen, a glypican3 antigen, a mesothelin antigen, a carcinoembryonic antigen (CEA), a prostate stem cell antigen (PSCA), and a CD70 antigen.
Yang et al further teaches carcinoembryonic antigen (CEA) as a CAR target for gastric cancer in clinical trials (Table I and Page 5686 paragraph 2), as is relevant to claim 18.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application to combine the gastrin vaccine and the CAR-T therapy taught by Yang et al into the methods of treating gastrointestinal tumors and sensitizing gastrointestinal tumors to anti-tumor T cell penetration taught by Sutton et al, in light of the teachings by Yang et al that gastrin vaccines and CAR-T therapies specifically, and combination therapies comprising of these therapies, have exhibited promising effects in the treatment of gastric cancers (Yang et al, Abstract) and other gastrin-associated cancers of the gastrointestinal tract (Yang et al, Page 5686, column 2, paragraph 2), arriving at the combination of compositions of claim of claims 11 and 19.
Further in light of the teachings of Yang et al that CAR-T therapies have been studied for treatment of solid tumors, specifically gastrointestinal tumors, in combination with the teachings of Sutton et al that their disclosed method of administering a gastrin vaccine to a gastric solid tumor increases endogenous T cell penetration into the tumor, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, that this method would likely also increase penetration of CAR-T cell therapies into the tumor microenvironment. As such, the method, having all the components of the method in claim 19 would also be expected, to sensitize a tumor to CAR-T cell penetration, arriving at all the claim limitations of claim 19.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to specifically choose as the CAR antigen target, a gastrointestinal cancer-related antigen, such as carcinoembryonic antigen (CEA), which Yang et al teaches has already been studied as a successful CAR target in gastrointestinal cancer therapy (Table 1 and Page 5686, paragraphs 2 and 4), arriving at all the limitations of claims 18 and 33.
One skilled in the art, before the effective filing date of the instant application, would be motivated to combine the gastrin vaccine and CAR-T cell therapy since both are taught to be successful in gastrointestinal solid tumors by Yang et al, and Sutton et al teaches the gastrin vaccine enhances tumor penetration by anti-tumor T cell, which would likely extend to CAR-T cells, providing a motivation to combine the two therapies over individual monotherapy, as is relevant to claims 11 and 19. One skilled in the art, before the effective filing date of the instant application, would be motivated to specifically choose CAR’s against known gastrointestinal tumor-related antigens, and specifically one that has already been used successful in CAR-T cell therapies in gastrointestinal cancers, such as the antigen CEA, as is relevant to claims 18 and 33.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success combining the gastrin vaccine and CAR-T cell therapy into methods of treating tumors and sensitizing tumors to CAR-T therapy since both therapies individually have shown efficacy in treating gastrointestinal cancers/tumors, as taught by Yang et al, and there is likely additional benefits to combining them, as evidenced by the results of Sutton et al discussed previously, as is relevant to claims 11 and 19. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success choosing CEA as the antigen that the CAR binds to since it has already been used successful in CAR-T cell therapies in gastrointestinal cancers, as is relevant to claims 18 and 33.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. In this case, the gastrin vaccine and the CAR-T therapies were both taught to be individually efficacious in gastrointestinal cancers, thus combining them for treatment in gastrointestinal cancers is an obvious treatment variant, especially in light of the potential synergistic effects taught in the art. One skilled in the art, before the effective filing date of the instant application, could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately. Although, Sutton et al alludes to potential synergistic effects of the combination therapy, related to the increased penetration of T cells into tumors conferred by gastrin vaccine treatment, amounting to greater effects than each therapy as a monotherapy, each therapy is still performing the same expected function, just at a potentially more effective capacity. One skilled in the art, before the effective filing date of the instant application, would have recognized that the results of the combination were predictable in light of the teachings of increased endogenous anti-tumor T cell penetration into tumors implying the potential to increase penetration of CAR-T cells.
The teachings to administer the gastrin immunogen conjugated to an immune carrier combined with the rationale and teachings to also administer an anti-tumor/cancer T cell, specifically a CAR-T cell, as taught by Pat ‘576 claims in view of Sutton et al and further in view of Yang et al, arrives at all the limitations of instant claims 11 and 19 and their dependent claims 12-17, 20-25, 30-31.
Claims 26-29 depend on claim 19. The teachings of the references regarding claim 19 are incorporated in its entirety for claims 26-29, and discussed further, as is relevant, for each claim below.
Regarding instant claims 26-29, Pat ‘576 claims 6-8 further teach the additional anti-tumor/anti-cancer therapies, that it could be an immune checkpoint inhibitor, the target polypeptides of these immune checkpoint inhibitors, and the specific immune checkpoint inhibitors by name or designation.
Regarding instant claim 32, Pat ‘576 and Sutton et al does not explicitly teach the one or more additional anti-tumor and/or anti-cancer therapies is administered subsequent to the administration of at least the first dose of the composition.
However, Yang et al teaches that anti-tumor/anti-cancer therapies, specifically immune checkpoint inhibitors, gastrin immunogen conjugated to an immunogenic carrier, and CAR-T cell therapies have individually had varying success in treating gastrointestinal cancers (Abstract, whole document). Sutton et al further teaches that gastrointestinal cancers, such as pancreatic cancer, have dense fibrotic networks that may limit penetration by immunotherapeutics, which could help to explain why checkpoint inhibitors have been characterized by very modest efficacy (Page 59, paragraphs 1-2). Sutton et al specifically teaches that gastrin vaccine and immune checkpoint inhibitors when administered together can provide synergistic effects to make tumors more accessible to immune checkpoint inhibitor drugs by reducing the fibrosis around solid tumors (Page 59, paragraph 2). Even though Sutton et al teaches co-administration and does not explicitly teach subsequent administration of the two components, the teachings of Sutton et al allude to a rationale for delaying administration of immune checkpoint inhibitors until after the tumor microenvironment has been made more permeable to penetration, for example, by administration of one of the other therapies, such as the gastrin vaccine, arriving at all the limitations of claim 32.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that not only is subsequent administration of the therapies an option, it may be desirable over co-administration, as the efficacy of the immune checkpoint inhibitor might not be working to its full potential before the fibrotic network is first reduced by, for example, the gastrin vaccine, especially in light of the teaching by Sutton et al that teaches that gastrin vaccine itself does reduce fibrosis and increases tumor microenvironment permeability to, for example, anti-tumor T cells.
One skilled in the art, before the effective filing date of the instant application, would be motivated to administer the immune checkpoint inhibitor or other anti-tumor therapies after the fibrotic network is reduced first to prevent potential wasteful administration of these drugs during earlier treatment times when they may not be most efficacious. One skilled in the art, before the effective filing date of the instant application, would be motivated to delay administration of the third anti-tumor therapy, such as checkpoint inhibitors, until there is reason to believe they can more effectively penetrate the tumor microenvironment.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success in light of the teachings by Sutton et al that immune checkpoint inhibitors have suffered from only moderate efficiency potentially due to inability to physically penetrate the fibrotic network of the tumor microenvironment and that gastrin vaccine monotherapy itself works to reduce the fibrotic network of the tumor microenvironment.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that if some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, then the combination is obvious. In this case, the motivation to sequentially administer the third therapeutic, such as an immune checkpoint inhibitor, is provided by its known efficacy shortcoming and the potential benefit that could be provided by administering it after another therapeutic had time to increase access into the tumor microenvironment. There is reasonable expectation of success because the first therapeutic, the gastrin vaccine, effectively increases access into the tumor microenvironment, even as a monotherapy, which could reasonably be expected to help increase the efficacy of subsequently administered therapeutics.
Patent US12076383B2:
Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. US12076383B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant disclosure defines a tumor to include all precancerous and cancerous cells, any neoplastic cell growth, whether malignant or benign (Specification, page 20).
Regarding instant claim 1, Pat ‘383 claims 1, 7 and 9 teach a method of administering a gastrin immunogen conjugated to an immunogenic carrier to prevent, reduce, and/or eliminate formation of fibrosis associated with pancreatic cancer/tumor, to increase anti-tumor T cells infiltration, or to prevent, reduce, and/or eliminate metastasis of gastrin-associated pancreatic cancer/tumor, which inherently will have the intended effects of enhancing other anti-tumor/cancer immunotherapeutics, thereby arriving at all the limitations of instant claim 1.
Instant claims 2-8 depend on instant claim 1. The teachings of the references regarding instant claim 1 are incorporated in its entirety for instant claims 2-8, and discussed further, as is relevant, for each claim below.
Regarding instant claim 2-3, Pat ‘383 claims 1 further teach pancreatic cancer/tumor.
Regarding instant claim 4, Pat ‘383 claim 2 further teaches the immunogenic carrier options.
Regarding instant claim 5, Pat ‘383 claim 3 further teaches the linker comprises a ɛ-maleimido caproic acid N-hydroxysuccinimide ester.
Regarding instant claim 6, Pat ‘383 claim 4 further teaches the amino acid spacer.
Regarding instant claim 7, Pat ‘383 claim 5 further teaches the adjuvant.
Regarding instant claim 8, Pat ‘383 claim 1 further teaches the gastrin peptide sequences.
Regarding instant claims 9-10, App ‘383 teaches a method using a composition comprising of a conjugate comprising a gastrin immunogen, thereby teaching the composition of claims 9-10.
Claims 11-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. US12076383B2 in view of Sutton et al and further in view of Yang et al.
Regarding instant claims 11-33, Pat ‘383 claims 1-9 teach the limitations regarding a method comprising of administering a gastrin immunogen conjugated to an immunogenic carrier to a gastrin-associated gastrointestinal cancer/tumor.
Pat ‘383 does not explicitly teach the method also comprises of administering a second composition comprising of an anti-tumor/cancer T cell, or specifically a CAR-T cell targeted against an antigen present on the tumor/cancer.
However, regarding claim 11, Sutton teaches a method for treating a tumor and/or cancer, optionally a gastrin- associated tumor and/or cancer and/or a gastrin-responsive tumor and/or cancer, in a subject, the method comprising: administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker, in an amount and via a route sufficient to enhance anti-tumor and/or anti-cancer T cell entry into the tumor and/or cancer, whereby the tumor and/or the cancer is treated (Section VI.A. Methods for Treating Gastrin-associated Tumors and/or Cancers; VI. E. Methods for Modulating T Cell Subpopulations in Subjects and Tumors Present Therein; and Example 6).
Regarding claim 19, Sutton teaches a method comprising:(a) administering to the subject a first composition comprising, consisting essentially of, or consisting of a conjugate comprising, consisting essentially of, or consisting of a gastrin immunogen conjugated to an immunogenic carrier, optionally conjugated via a linker.
As is relevant to claims 11 and 19, Sutton et al does not explicitly teach the method further comprises administering to the subject a second composition comprising an anti-tumor and/or anti-cancer T cell, and in particular for claim 19, wherein the anti-tumor and/or anti-cancer T cell comprises a chimeric antigen receptor (CAR) that binds to a tumor-associated and/or cancer-associated antigen present on the tumor and/or the cancer.
As is relevant to claim 19, Sutton et al does not explicitly teach the method for sensitizing a solid tumor and/or cancer in a subject to a chimeric antigen receptor-T (CAR-T) cell therapy, and that the composition is administered in an amount and via a route sufficient to enhance entry of the CAR-T cell into the solid tumor and/or cancer.
However, Yang et al teaches that cancer vaccines, CAR-T cell therapy, and immune checkpoint inhibitors, as well as combination therapy comprising of these immunotherapies, are specifically useful in gastric cancers (Abstract, whole document), as is relevant to claims 11 and 19. Additionally, Sutton et al further teaches that fibrosis in the tumor microenvironment could be implicated in preventing immunotherapy penetration and that the gastrin immunogen conjugated to an immunogenic carrier taught in their method is able to reduce fibrosis in the tumor microenvironment and enhance endogenous anti-tumor T cell penetration into the tumor microenvironment (Page 59, paragraph 2; Examples 5 and 6).
Claims 18 and 33 depend on claim 11. The teachings of the references regarding claim 11 are incorporated in its entirety for claim 18 and 33, and discussed further, as is relevant, for each claim below.
Regarding instant claim 18 and 33, Pat ‘383 does not explicitly teach the CAR’s target antigen.
As is relevant to claims 18 and 33, Sutton et al does not explicitly teach wherein the CAR binds to an antigen selected from the group consisting of a claudin18.2 antigen, a glypican3 antigen, a mesothelin antigen, a carcinoembryonic antigen (CEA), a prostate stem cell antigen (PSCA), and a CD70 antigen.
Yang et al further teaches carcinoembryonic antigen (CEA) as a CAR target for gastric cancer in clinical trials (Table I and Page 5686 paragraph 2), as is relevant to claim 18.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application to combine the gastrin vaccine and the CAR-T therapy taught by Yang et al into the methods of treating gastrointestinal tumors and sensitizing gastrointestinal tumors to anti-tumor T cell penetration taught by Sutton et al, in light of the teachings by Yang et al that gastrin vaccines and CAR-T therapies specifically, and combination therapies comprising of these therapies, have exhibited promising effects in the treatment of gastric cancers (Yang et al, Abstract) and other gastrin-associated cancers of the gastrointestinal tract (Yang et al, Page 5686, column 2, paragraph 2), arriving at the combination of compositions of claim of claims 11 and 19.
Further in light of the teachings of Yang et al that CAR-T therapies have been studied for treatment of solid tumors, specifically gastrointestinal tumors, in combination with the teachings of Sutton et al that their disclosed method of administering a gastrin vaccine to a gastric solid tumor increases endogenous T cell penetration into the tumor, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, that this method would likely also increase penetration of CAR-T cell therapies into the tumor microenvironment. As such, the method, having all the components of the method in claim 19 would also be expected, to sensitize a tumor to CAR-T cell penetration, arriving at all the claim limitations of claim 19.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to specifically choose as the CAR antigen target, a gastrointestinal cancer-related antigen, such as carcinoembryonic antigen (CEA), which Yang et al teaches has already been studied as a successful CAR target in gastrointestinal cancer therapy (Table 1 and Page 5686, paragraphs 2 and 4), arriving at all the limitations of claims 18 and 33.
One skilled in the art, before the effective filing date of the instant application, would be motivated to combine the gastrin vaccine and CAR-T cell therapy since both are taught to be successful in gastrointestinal solid tumors by Yang et al, and Sutton et al teaches the gastrin vaccine enhances tumor penetration by anti-tumor T cell, which would likely extend to CAR-T cells, providing a motivation to combine the two therapies over individual monotherapy, as is relevant to claims 11 and 19. One skilled in the art, before the effective filing date of the instant application, would be motivated to specifically choose CAR’s against known gastrointestinal tumor-related antigens, and specifically one that has already been used successful in CAR-T cell therapies in gastrointestinal cancers, such as the antigen CEA, as is relevant to claims 18 and 33.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success combining the gastrin vaccine and CAR-T cell therapy into methods of treating tumors and sensitizing tumors to CAR-T therapy since both therapies individually have shown efficacy in treating gastrointestinal cancers/tumors, as taught by Yang et al, and there is likely additional benefits to combining them, as evidenced by the results of Sutton et al discussed previously, as is relevant to claims 11 and 19. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success choosing CEA as the antigen that the CAR binds to since it has already been used successful in CAR-T cell therapies in gastrointestinal cancers, as is relevant to claims 18 and 33.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that combining prior art elements according to known methods to yield predictable results is obvious. The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. In this case, the gastrin vaccine and the CAR-T therapies were both taught to be individually efficacious in gastrointestinal cancers, thus combining them for treatment in gastrointestinal cancers is an obvious treatment variant, especially in light of the potential synergistic effects taught in the art. One skilled in the art, before the effective filing date of the instant application, could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately. Although, Sutton et al alludes to potential synergistic effects of the combination therapy, related to the increased penetration of T cells into tumors conferred by gastrin vaccine treatment, amounting to greater effects than each therapy as a monotherapy, each therapy is still performing the same expected function, just at a potentially more effective capacity. One skilled in the art, before the effective filing date of the instant application, would have recognized that the results of the combination were predictable in light of the teachings of increased endogenous anti-tumor T cell penetration into tumors implying the potential to increase penetration of CAR-T cells.
The teachings to administer the gastrin immunogen conjugated to an immune carrier combined with the rationale and teachings to also administer an anti-tumor/cancer T cell, specifically a CAR-T cell, as taught by Pat ‘383 claims in view of Sutton et al and further in view of Yang et al, arrives at all the limitations of instant claims 11 and 19 and their dependent claims 12-17, 20-25, 30-31.
Claims 26-29 depend on claim 19. The teachings of the references regarding claim 19 are incorporated in its entirety for claims 26-29, and discussed further, as is relevant, for each claim below.
Regarding instant claims 26-29, Pat ‘383 claims 1, 6-9 further teach the additional anti-tumor/anti-cancer therapies, that it could be an immune checkpoint inhibitor, the target polypeptides of these immune checkpoint inhibitors, and the specific immune checkpoint inhibitors by name or designation.
Regarding instant claim 32, Pat ‘383 and Sutton et al does not explicitly teach the one or more additional anti-tumor and/or anti-cancer therapies is administered subsequent to the administration of at least the first dose of the composition.
However, Yang et al teaches that anti-tumor/anti-cancer therapies, specifically immune checkpoint inhibitors, gastrin immunogen conjugated to an immunogenic carrier, and CAR-T cell therapies have individually had varying success in treating gastrointestinal cancers (Abstract, whole document). Sutton et al further teaches that gastrointestinal cancers, such as pancreatic cancer, have dense fibrotic networks that may limit penetration by immunotherapeutics, which could help to explain why checkpoint inhibitors have been characterized by very modest efficacy (Page 59, paragraphs 1-2). Sutton et al specifically teaches that gastrin vaccine and immune checkpoint inhibitors when administered together can provide synergistic effects to make tumors more accessible to immune checkpoint inhibitor drugs by reducing the fibrosis around solid tumors (Page 59, paragraph 2). Even though Sutton et al teaches co-administration and does not explicitly teach subsequent administration of the two components, the teachings of Sutton et al allude to a rationale for delaying administration of immune checkpoint inhibitors until after the tumor microenvironment has been made more permeable to penetration, for example, by administration of one of the other therapies, such as the gastrin vaccine, arriving at all the limitations of claim 32.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that not only is subsequent administration of the therapies an option, it may be desirable over co-administration, as the efficacy of the immune checkpoint inhibitor might not be working to its full potential before the fibrotic network is first reduced by, for example, the gastrin vaccine, especially in light of the teaching by Sutton et al that teaches that gastrin vaccine itself does reduce fibrosis and increases tumor microenvironment permeability to, for example, anti-tumor T cells.
One skilled in the art, before the effective filing date of the instant application, would be motivated to administer the immune checkpoint inhibitor or other anti-tumor therapies after the fibrotic network is reduced first to prevent potential wasteful administration of these drugs during earlier treatment times when they may not be most efficacious. One skilled in the art, before the effective filing date of the instant application, would be motivated to delay administration of the third anti-tumor therapy, such as checkpoint inhibitors, until there is reason to believe they can more effectively penetrate the tumor microenvironment.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success in light of the teachings by Sutton et al that immune checkpoint inhibitors have suffered from only moderate efficiency potentially due to inability to physically penetrate the fibrotic network of the tumor microenvironment and that gastrin vaccine monotherapy itself works to reduce the fibrotic network of the tumor microenvironment.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that if some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, then the combination is obvious. In this case, the motivation to sequentially administer the third therapeutic, such as an immune checkpoint inhibitor, is provided by its known efficacy shortcoming and the potential benefit that could be provided by administering it after another therapeutic had time to increase access into the tumor microenvironment. There is reasonable expectation of success because the first therapeutic, the gastrin vaccine, effectively increases access into the tumor microenvironment, even as a monotherapy, which could reasonably be expected to help increase the efficacy of subsequently administered therapeutics.
Conclusion
No claims are allowed.
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/B.C./Examiner, Art Unit 1645 February 26, 2026
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645