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 .
Priority
U.S. Provisional Application 63/445,872, filed February 15, 2023, discloses administering 25 μg/g doses of mifepristone in the in vivo mouse model Example. However, the 63/445,872 does not teach 100-400 mg/day dosing.
Thus, claims 1-16 are examined with the effective filing date of February 15, 2023 and claim 17 is examined with the actual filing date of February 15, 2024.
Should Applicant disagree with the analysis above, he or she should point to the page and line of U.S. Provisional Application 63/445,872 which teaches 100-400 mg/day dosing.
Claim Objections
Claims 1, 3, 5, and 10-13 are objected to because of the following informalities:
Claim 1 recites “A method of the treatment of cancer”, but should more properly recite “A method of treating cancer”.
Claim 3 recites “fetal/placental unit”. The / is used to indicate alternatives, but this contradicts the common meaning of unit, which indicates components combined as one. Examiner suggests replacing with “fetal-placental unit”.
Claim 5 lines 13 and 14 recite “1L-6” and “1L-10”, but should be “IL-6” and “IL-10”. Line 11, for example, recites “TGF-.alpha. receptor” with periods before and after the Greek letter. The periods before and after Greek letters should be removed throughout.
Claim 5 lines 21-22 needs clear spacing and punctuation and corrected spelling. It should be “low density lipid receptor – GDP-L-fucose: beta-D-galactoside 2-alpha-L-fucosyltransferase fusion protein”. Similarly, other fusion proteins recited should separate fusion protein components by a hyphen (-), not a slash (/) as the latter generally indicates alternatives.
In claim 5 line 32, “S1LV” should be “SILV”. Additionally, gp100, PME117, and SILV are synonyms yet appear to be listed as alternatives; see 112b below.
Claim 5 line 27 recites “BAGE-2, 3, 4, 5” and should be written out “BAGE-2, BAGE-3, BAGE-4, BAGE-5” where the “,” is whatever punctuation (i.e. comma or semicolon) Applicant wishes to consistently use throughout the claim to separate alternatives. Repeat for GAGE-1, etc. in line 27, SSX-1, etc. in line 33.
Punctuation is problematic throughout claim 5 and Applicant should be consistent using either a comma or semicolon to separate list items. Presently, commas, colons, semicolons, periods, or no punctuation separate list items and cause indefiniteness; see 112b below. For example, line 37 is missing punctuation in “glycoprotein 250 (gp250intestinal carboxyl esterase (iCE)”; also see 112b section. Similarly, “TRP-2 adipophilin” in line 35 and “NXF2 TDRD1” in line 42 are missing punctuation. This is not an exhaustive list. Applicant should carefully review punctuation throughout the claim.
Claim 5 line 35 recites “TRP-1/, 75” and should be “TRP-1”. Additionally, TRP-1 is already listed in line 32.
In claim 10, “indolamine 2,3 dioxygenase” should be “indoleamine 2,3 dioxygenase”.
Claims 11-13 appear to further limit indoleamine 2,3 dioxygenase of claim 10, but refer to it as “2,3 dioxygenase”. Claims 11-13 should use the full name or the art recognized abbreviation “IDO”. “2,3 dioxygenase” could similarly refer to indolamine-2,3-dioxygenase 2 (IDO2) or tryptophan 2,3-dioxygenase (TDO).
Appropriate correction is required.
Applicant is advised that should claim 11 be found allowable, claim 13 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 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 1-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “administration of one or more abortogenic agents combined with one or more immunotherapies.” Administration is a noun and thus the claim does not recite any active steps. It is unclear whether or not the claimed method requires administering the two agents. For the purpose of compact prosecution, the method is interpreted as requiring administering at least one abortogenic agent and at least one immunotherapy.
Additionally, claim 1 does not recite a subject or patient receiving the treatment. It is unclear whether one subject or one patient must be treated with the regimen or whether all cancer must be treated to infringe. For the purpose of compact prosecution, claim 1 is interpreted as requiring the treatment of one subject.
Claims 2-17 are rejected for depending from claim 1 and failing to remedy the indefiniteness.
Claim 2 recites that the abortogenic agent stimulates “pregnancy resorption/loss”. It is unclear whether pregnancy resorption, pregnancy loss, or both are required. For the purpose of compact prosecution, claim 2 is interpreted as requiring either.
Claim 3 depends from claim 2 and similarly recites “pregnancy resorption/loss”.
Claim 5 lines 12-13 recites “Interleukin .beta. receptor alpha2 chain (IL13Ralpha2)”. What is recited before the parenthesis does not match what is recited within the parenthesis. Are both required? Is only one required? What is the parenthesis here indicating? Additionally, which interleukin beta is being recited before the parenthesis? There should be a number between “interleukin” and “beta”. For the purpose of compact prosecution, this limitation is interpreted as requiring “interleukin 1 beta receptor” or “interleukin 13 receptor alpha 2”. In the context of the claim as a whole, “interleukin 1 beta receptor” and “interleukin 13 receptor alpha 2” are interpreted as alternatives within a list of many, of which only a single alternative from this list is required.
Claim 5 contains parentheticals and slashes. For example, “epidermal growth factor receptor (EGFR, EGFR1, ErbB-1, HER1)”, “ErbB-2 (HER2/neu)”, etc. The parentheticals and slashes make unclear whether one of the species in parentheses are required or whether the species serve as an exemplary list.
Claim 5 line 33 recites “TRP2-1NT2”. Tyrosinase-related Protein 2, also known as TRP-2, is understood, but it is unclear the significance of “-1NT2”. Is this denoting a fusion protein or complex which comprises TRP2? What is 1NT2?
Claim 5 line 32-33 recites “NA-88”. It is unclear what to “NA-88” refers?
Claim 5 separates selections in the group listed by commas, semicolons, and colons. Line 7, for example, contains all three punctuations. It is unclear if there are sublists within the larger group listing. If there are sublists, then is a selection required from only the sublist or are those exemplary items?
For the purpose of compact prosecution, every word in claim 5 separated by a comma, colon, semi-colon, slash, or parenthesis is interpreted as a discrete selection or alternative within the list of alternatives with only one needing to be selected to meet the claim.
Claims 6-8 recite the limitations “the progesterone signaling pathway” or “the glucocorticoid signaling pathway”. There is insufficient antecedent basis for this limitation in the claim. Additionally, it is unclear whether these limitations only limit the abortogenic agent used or do they also limit the subject being treated. For example, in humans, males do not produce progesterone and there are several conditions which result in deficiencies of the progesterone signaling pathway or the glucocorticoid signaling pathway. Do these claims require that the subject has this these pathways inherently present? Claim 1 from which these claims depend does not require administering into a female patient nor does the claim require administering to a human. In other words, does the abortogenic agent need to function as an inhibitor of the progesterone signaling pathway and/or the glucocorticoid signaling pathway in the subject to which it is administered?
Claim 12 contains the trademark/trade name quadramune. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a composition and, accordingly, the identification/description is indefinite.
There is no definition for quadramune in the instant disclosure which discloses the structure of the claimed composition.
Claim 17 recites administering mifepristone at a dose of 100-400 mg/day. The “/day” without recitation of a dose frequency or duration makes unclear whether a single 100-400mg dose meets the claim or whether 100-400mg daily dosing is required. For the purpose of compact prosecution, claim 17 is interpreted a requiring a single dose or aggregate doses totaling 100-400 mg in a single day - repeated dosing (e.g. daily) is not required.
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 1-3, 6-9, and 17 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ma et al. (US 2025/0032506 A1; Effectively Filed: December 5, 2022; Published: January 30, 2025) as evidenced by Li et al. (Reproductive and Developmental Medicine. 4(2): 63-71; Published: June 25, 2020) and Spitz et al. (The New England Journal of Medicine. 329: 404-412; Published: August 5, 1993).
Regarding claims 1, 7, and 9, Ma et al. teaches a method of treating a subject having pancreatic cancer that does not respond to an immune checkpoint inhibitor (ICI) therapy comprising administering one or more glucocorticoid receptor antagonists and one or more ICI therapeutics selected from an anti-PD-1, an anti-PD-L1, or and an anti-CTLA-4; wherein the glucocorticoid receptor antagonist is mifepristone; see claims 1, 11, 25, and 27.
Regarding claim 17, Ma et al. teaches a total daily dose of mifepristone of about 100mg to about 2500mg; see paragraphs 0099-0100.
Regarding claims 2 and 3, Li et al. evidences that mifepristone induced abortion results in a significantly higher number of decidual (i.e. placental) macrophages and elevated levels of CD4+ T cells and IFN-gamma; see Abstract.
Regarding claims 6 and 8, Spitz et al. evidences that mifepristone inhibits progesterone and glucocorticoids; see page 404 right column and page 408 right column.
Thus, claims 1-3, 6-9, and 17 are anticipated by Ma et al. as evidenced by Li et al. and Spitz et al.
Claims 1, 14, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Page et al. (Neuro-Oncology. 20(Suppl 2):i120; Published: June 22, 2018) as evidenced by Ozeren et al. (Contraception. 59: 389-394; Published: September 20, 1999) and Wen et al. (Cell Reports. 38: 110301; Published: January 25, 2022).
Regarding claim 1, Page et al. teaches treating pediatric brain tumors comprising administering a combination regimen which comprises methotrexate and bevacizumab; see Methods.
Ozeren et al. evidences that methotrexate can be used as an abortigenic agent; see Abstract, for example.
Regarding claims 14 and 15, Wen et al. evidences that bevacizumab, an anti-VEGF antibody, is an anti-angiogenic immunotherapy which results in endothelial cell death; see page 1 left column and Abstract. Since the mechanism of action centers around endothelial cells, the therapy is an endothelial cell based therapy.
Thus, claims 1, 14, and 15 are anticipated by Page et al. as evidenced by Ozeren et al. and Wen et al.
Claims 1-3, 6-9, 14, 15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Check et al. (Cancer Research. 78 (13_Supplement): Abstract 4715; Published: July 1, 2018) as evidenced by Li et al. (Reproductive and Developmental Medicine. 4(2): 63-71; Published: June 25, 2020), Spitz et al. (The New England Journal of Medicine. 329: 404-412; Published: August 5, 1993), and Wen et al. (Cell Reports. 38: 110301; Published: January 25, 2022).
Claim 1 is drawn to a method of treating cancer comprising administering one or more abortogenic agent and one or more immunotherapy. While the claim recites one or more abortogenic agent “combined with” one or more immunotherapy, there is no limiting definition for combined in the instant disclosure and thus, it is interpreted as both the abortogenic agent and immunotherapy administered to an individual. The claim does not require that both the abortogenic agent and immunotherapy be given within a particular time frame of one another.
Regarding claims 1 and 9, Check et al. teaches a patient having NSCLC having been treated with the immunotherapies, bevacizumab and nivolumab, followed by the abortogenic agent, mifepristone. Check et al. teaches that mifepristone treatment resulted in a slight reduction in some metastatic lesions and no development of new metastatic lesions.
Regarding claim 17, the patient was treated with 300mg/day of mifepristone for one year.
Regarding claims 2 and 3, Li et al. evidences that mifepristone induced abortion results in a significantly higher number of decidual (i.e. placental) macrophages and elevated levels of CD4+ T cells and IFN-gamma; see Abstract.
Regarding claims 6-8, Spitz et al. evidences that mifepristone inhibits progesterone and glucocorticoids; see page 404 right column and page 408 right column.
Regarding claims 14 and 15, Wen et al. evidences that bevacizumab, an anti-VEGF antibody, is an anti-angiogenic immunotherapy which results in endothelial cell death; see page 1 left column and Abstract. Since the mechanism of action centers around endothelial cells, the therapy is an endothelial cell-based therapy.
Thus, claims 1-3, 6-9, 14, 15, and 17 are anticipated by Check et al. as evidenced by Li et al., Spitz et al., and Wen et al.
Claims 1-4 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alahdal et al. (Scientific Reports. 8:9869; Published: June 29, 2018) as evidenced by Mellor et al. (Journal of Reproductive Immunology. 52: 5-13; Published Online: October 8, 2001).
Regarding claims 1 and 10, Alahdal et al. teaches treating cancer comprising administering the IDO inhibitor, 1-methyl-tryptophan (as known as 1-MT), and a tumor autologous antigens vaccine; see Abstract. Alahdal et al. teaches that 1-MT supports immunotherapeutic vaccines susceptibility and tumor specific targeting by reducing tumorigenic signaling pathways; see Abstract and Figure 5, for example.
Regarding claims 2 and 3, Mellor et al. evidences that expression of indoleamine 2,3-dioxygenase (IDO) protected allogeneic murine fetuses from lethal maternal immune responses; see Section 2. Further, Mellor et al. evidences that mothers exposed to higher doses (10 mg/mouse per day) of 1-methyl-tryptophan rejected all their allogeneic fetuses before birth; see Section 3. Histologic examination of the maternal-fetal interface in mice bearing fetal allografts and exposed to 1-methyl-tryptophan revealed extensive inflammation, cellular infiltration and hemorrhagic necrosis; see Section 4
Regarding claim 4, Alahdal et al. teaches that the tumor lysate vaccine was prepared using Pan02 cells and mice were immunized subcutaneously with tumor lysate mixed with aluminum hydroxide gel, an adjuvant; see page 11.
Thus, claims 1-4 and 10 are anticipated by Alahdal et al. as evidenced by Mellor et al.
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 5, 14, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Alahdal et al. (Scientific Reports. 8:9869; Published: June 29, 2018) as evidenced by Mellor et al. (Journal of Reproductive Immunology. 52: 5-13; Published Online: October 8, 2001) as applied to claim(s) 1-4 and 10 above, and in view of Kim et al. (Nature Communications. 13: 6292; Published Online: October 22, 2022) and Gavilondo et al. (Vaccine. 32(19): 2241-2250; Published Online: February 11, 2014).
The teachings of Alahdal et al. as evidenced by Mellor et al. as related to claim(s) 1-4 and 10, from which these claims depend are given previously in this Office action and are fully incorporated here.
Alahdal et al. does not teach which tumor or tumor endothelial antigens are present in the vaccine. Nor that the effects are anti-angiogenic or endothelial cell based.
Regarding claim 5, Kim et al. teaches that Pan02 tumors express VEGF; see Figure 1, for example.
Kim et al. does not teach anti-angiogenic or endothelial cell based effects of the Pan02 tumor lysate vaccine.
Gavilondo et al. teaches treating cancer with a therapeutic cancer vaccine comprising VEGF as an antigen with 12 of 30 patients demonstrating objective response; see Abstract, for example. Regarding claims 14 and 15, Gavilondo et al. teaches vaccines comprising VEGF are anti-angiogenic therapies that result in the development of polyclonal antibodies against VEGF that block its interaction with VEGFR on endothelial cells. Since the mechanism of action works, in part, by blocking signaling in endothelial cells, a vaccine comprising VEGF is endothelial cell based.
It would have been obvious to one of ordinary skill in the art that administering a tumor lysate vaccine would comprise VEGF as one of the antigens since Kim et al. teaches that Pan02 tumors express VEGF. Gavilondo et al. teaches treating cancer with a therapeutic cancer vaccine comprising VEGF as an antigen with 12 of 30 patients demonstrating objective response, thus one of ordinary skill would have had a reasonable expectation of success treating with an anti-angiogenic immunotherapy wherein the tumor lysate vaccine comprises VEGF as an antigen.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Alahdal et al. (Scientific Reports. 8:9869; Published: June 29, 2018) as evidenced by Mellor et al. (Journal of Reproductive Immunology. 52: 5-13; Published Online: October 8, 2001) as applied to claim(s) 1-4 and 10 above, and in view of Ichim et al. (US 11,229,674 B1; Published: January 25, 2022).
The teachings of Alahdal et al. as evidenced by Mellor et al. as related to claim(s) 1-4 and 10, from which these claims depend are given previously in this Office action and are fully incorporated here.
Alahdal et al. does not teach that the abortogenic agent is the indolamine 2,3 dioxygenase inhibitor Quadramune.
Ichim et al. teaches that Quadramune comprises pterostilbene, Nigella sativa extract, green
tea extract, and broccoli for reduction in activity of indolamine 2,3 dioxygenase; see column 4, for example. Further, Ichim et al. teaches a method of inhibiting indolamine 2,3 dioxygenase (IDO) expression or activity, comprising: administration to a patient in need a therapeutic combination comprising: a) Green Tea and/or extract thereof; b) Blueberry and/or extract thereof; c) Nigella sativa and/or extract thereof; and d) broccoli and/or extract thereof; see claims 1 and 3, for example. Ichim et al. teaches that the method is use in a patient suffering from a tumor; see claims 15 and 16.
Given that Alahdal et al. teaches treating cancer with a combination regimen comprising 1-MT, an IDO inhibitor, and Ichim et al. teaches treating cancer with Quadramune, an IDO inhibitor, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success substitution Quadramune taught by Ichim et al. for 1-MT in the combination method taught by Alahdal et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Alahdal et al. (Scientific Reports. 8:9869; Published: June 29, 2018) as evidenced by Mellor et al. (Journal of Reproductive Immunology. 52: 5-13; Published Online: October 8, 2001) as applied to claim(s) 1-4 and 10 above, and in view of Cundy et al. (RSC Chemical Biology. 2(6): 1651-1660; Published: September 13, 2021).
The teachings of Alahdal et al. as evidenced by Mellor et al. as related to claim(s) 1-4 and 10, from which these claims depend are given previously in this Office action and are fully incorporated here.
Alahdal et al. does not teach administering 2-methyl-tryptophan (2-MT).
Cundy et al. teaches proposed new mechanistic pathways of radical and electrophilic IDO1 mediated dioxygenation of L-tryptophan to inform the design of new substrate mimics to serve as IDO inhibitors. Scheme 3 depicts the dioxygenation of L-tryptophan with the formation of an experimentally validated epoxide intermediate at carbons 2 and 3 of indole ring.
Given that 2-methyl-tryptophan is an isomer of 1-mt with the methyl group attached to carbon 2 of the indole ring, it would have been obvious and one would have had a reasonable expectation of success to substitution 2-methyl-tryptophan in place of 1-methyl-tryptophan as a IDO substrate mimic in the method of treating cancer taught by Alahdal et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 1-3, 10, and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Alahdal et al. (Scientific Reports. 8:9869; Published: June 29, 2018) as evidenced by Mellor et al. (Journal of Reproductive Immunology. 52: 5-13; Published Online: October 8, 2001) and in view of Ichim et al. (Journal of Translational Medicine. 13: 90; Published: March 14, 2015).
Regarding claims 1 and 10, Alahdal et al. teaches treating cancer comprising administering the IDO inhibitor, 1-methyl-tryptophan (as known as 1-MT), and a tumor autologous antigens vaccine; see Abstract. Alahdal et al. teaches that 1-MT supports immunotherapeutic vaccines susceptibility and tumor specific targeting by reducing tumorigenic signaling pathways; see Abstract and Figure 5, for example.
Regarding claims 2 and 3, Mellor et al. evidences that expression of indoleamine 2,3-dioxygenase (IDO) protected allogeneic murine fetuses from lethal maternal immune responses; see Section 2. Further, Mellor et al. evidences that mothers exposed to higher doses (10 mg/mouse per day) of 1-methyl-tryptophan rejected all their allogeneic fetuses before birth; see Section 3. Histologic examination of the maternal-fetal interface in mice bearing fetal allografts and exposed to 1-methyl-tryptophan revealed extensive inflammation, cellular infiltration and hemorrhagic necrosis; see Section 4
Alahdal et al. teaches treating with a combination comprising the IDO inhibitor, 1-MT, and tumor lysate vaccine administered with IFN-gamma, but Alahdal et al. does not teach administering a vaccine comprising endothelial cells and IFN-gamma, nor comprising placental derived endothelial progenitor cells.
Regarding claims 14-16, Ichim et al. teaches treating cancer with “ValloVax”, an anti-angiogenic vaccine comprising IFN-gamma pretreated placental endothelial cells; see Abstract, for example. Ichim et al. teaches that “ValloVax” resulted in a significant reduction in tumor growth and metastasis; see Abstract, for example. Regarding claim 5, Ichim et al. teaches that placental endothelial cells are used as a polyvalent antigenic source and shares the following molecules with tumor endothelial cells: VEGF, placental growth factor, angiopoietin, FGF, EGF, and TGF-beta; see paragraph bridging page 6 and 7.
It would have been obvious to one of ordinary skill in the art to substitute “ValloVax” taught by Ichim et al. in place of the tumor lysate vaccine taught by Alahdal et al. in combination with 1-MT. One would have had a reasonable expectation of success and predictability because both “ValloVax” and the tumor lysate vaccine taught by Alahdal et al. aim to produce an immunogenic response to tumor or tumor endothelial antigens and Alahdal et al. demonstrates that the addition of 1-MT resulted in significantly decrease tumor size and increased survival. One would have been motivated to substitute “ValloVax” taught by Ichim et al. in place of the tumor lysate vaccine taught by Alahdal et al. because, in contrast to autologous tumor lysate, Ichim et al. demonstrates the therapeutic activity of “ValloVax” against a wide range of histologically distinct tumor types; see Figures 4 (melanoma), 5 (breast cancer), and 6 (lung cancer) for example.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 1-3, 6-9, and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Wagner et al. (US 2016/0206717 A1; Published: July 21, 2016) in view of Ma et al. (US 2025/0032506 A1; Effectively Filed: December 5, 2022; Published: January 30, 2025) and Ichim et al. (Journal of Translational Medicine. 13: 90; Published: March 14, 2015), and as evidenced by Li et al. (Reproductive and Developmental Medicine. 4(2): 63-71; Published: June 25, 2020) and Spitz et al. (The New England Journal of Medicine. 329: 404-412; Published: August 5, 1993).
Wagner et al. teaches cancer therapy by inhibiting tumor neovascularization or angiogenesis; see paragraph 0002. Regarding claims 1 and 14, Wagner et al. teaches one embodiment wherein “ValloVax” is used to induce immunity against tumor generated vasculature; see paragraph 0045. Regarding claims 1 and 9, Wagner et al. teaches that other anti-cancer agents can be used in conjunction with the immunotherapeutic targeting of tumor vasculature, including mifepristone; see paragraph 0057.
While Wagner et al. teaches how “ValloVax” is prepared (see paragraphs 0045-0047), the reference does not state that it comprises placental endothelial cells nor which antigens it comprises.
Ma et al. teaches the mifepristone can be combined to enhance the efficacy of immunotherapies, such as anti-PD-1 antibodies, in patients having pancreatic cancer that does not respond to an immune checkpoint inhibitor (ICI) therapy; see claims 1, 11, 25, and 27 . Ma et al. teaches that mifepristone reduces expression of immune inhibitory molecules and increases the expression of MHC-I molecules in pancreatic cancer; see Figure 9, for example.
Regarding claim 17, Ma et al. teaches a total daily dose of mifepristone of about 100mg to about 2500mg; see paragraphs 0099-0100.
Regarding claims 2 and 3, Li et al. evidences that mifepristone induced abortion results in a significantly higher number of decidual (i.e. placental) macrophages and elevated levels of CD4+ T cells and IFN-gamma; see Abstract.
Regarding claims 6- 8, Spitz et al. evidences that mifepristone inhibits progesterone and glucocorticoids; see page 404 right column and page 408 right column.
Ma et al. does not teach “ValloVax”, that it comprises placental endothelial cells nor which antigens it comprises
Regarding claims 14-16, Ichim et al. teaches treating cancer with “ValloVax”, a anti-angiogenic vaccine comprising IFN-gamma pretreated placental endothelial cells; see Abstract, for example. Ichim et al. teaches that “ValloVax” resulted in a significant reduction in tumor growth and metastasis; see Abstract, for example. Ichim et al. teaches that placental endothelial cells are used as a polyvalent antigenic source and shares the following molecules with tumor endothelial cells: VEGF, placental growth factor, angiopoietin, FGF, EGF, and TGF-beta; see paragraph bridging page 6 and 7.
It would have been obvious to one of ordinary skill in art and one would have had a reasonable expectation of success to treat cancer comprising administering mifepristone and “ValloVax” because Wagner et al. teaches combining other anti-cancer agents with “ValloVax”, including mifepristone. One would have been motivated to combine mifepristone and “ValloVax” because Ma et al. teaches that mifepristone reduced expression of immune inhibitory molecules while increasing expression of antigen presenting MHC-1 molecules and Ichim et al. teaches that “ValloVax” uses placental endothelial cells are used as a polyvalent antigenic source and Wagner et al. teaches that “ValloVax” can be used to treat a wide range of cancers; see Wagner et al. Figures 4 (melanoma), 5 (breast cancer), and 6 (lung cancer) paragraph bridging page 6 and 7, for example.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-4, 10, and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,229,674 B1 in view of Alahdal et al. (Scientific Reports. 8:9869; Published: June 29, 2018) as evidenced by Mellor et al. (Journal of Reproductive Immunology. 52: 5-13; Published Online: October 8, 2001).
Regarding instant claims 1 and 12, issued claims 1-16 teach a method of inhibiting indolamine 2,3 deoxygenase (IDO) expression or activity, comprising: administration to a patient in need a therapeutic combination comprising: a) Green Tea and/or extract thereof; b) Blueberry and/or extract thereof; c) Nigella sativa and/or extract thereof; and d) broccoli and/or extract thereof. Issued claims 15 and 16 teach that the method is use in a patient suffering from a tumor. Quadramune comprises pterostilbene, Nigella sativa extract, green tea extract, and broccoli for reduction in activity of indolamine 2,3 deoxygenase; see column 4, for example.
The issued claims do not teach a method of treating with an immunotherapy and Quadramune.
Regarding instant claims 1 and 10, Alahdal et al. teaches treating cancer comprising administering the IDO inhibitor, 1-methyl-tryptophan (as known as 1-MT), and a tumor autologous antigens vaccine; see Abstract. Alahdal et al. teaches that 1-MT supports immunotherapeutic vaccines susceptibility and tumor specific targeting by reducing tumorigenic signaling pathways; see Abstract and Figure 5, for example.
Regarding instant claims 2 and 3, Mellor et al. evidences that expression of indoleamine 2,3-dioxygenase (IDO) protected allogeneic murine fetuses from lethal maternal immune responses; see Section 2. Further, Mellor et al. evidences that mothers exposed to higher doses (10 mg/mouse per day) of 1-methyl-tryptophan rejected all their allogeneic fetuses before birth; see Section 3. Histologic examination of the maternal-fetal interface in mice bearing fetal allografts and exposed to 1-methyl-tryptophan revealed extensive inflammation, cellular infiltration and hemorrhagic necrosis; see Section 4
Regarding instant claim 4, Alahdal et al. teaches that the tumor lysate vaccine was prepared using Pan02 cells and mice were immunized subcutaneously with tumor lysate mixed with aluminum hydroxide gel, an adjuvant; see page 11.
Given that the issued claims teach a method of treating cancer comprising IDO inhibition by a composition comprising a combination of pterostilbene, Nigella sativa extract, green tea extract, and broccoli and the Specification teaches the Quadramune comprises the said combination and Alahdal et al. teaches treating cancer with a combination comprising an IDO inhibitor and a tumor lysate vaccine, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat cancer with the combination of Quadramune and a tumor lysate vaccine.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 5, 14, and 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,229,674 B1 in view of Alahdal et al. (Scientific Reports. 8:9869; Published: June 29, 2018) as evidenced by Mellor et al. (Journal of Reproductive Immunology. 52: 5-13; Published Online: October 8, 2001) as applied to claim(s) 1-4, 10, and 12 above, and further in view of Kim et al. (Nature Communications. 13: 6292; Published Online: October 22, 2022) and Gavilondo et al. (Vaccine. 32(19): 2241-2250; Published Online: February 11, 2014).
The teachings of U.S. Patent No. 11,229,674 B1 in view of Alahdal et al. as evidenced by Mellor et al. as related to claim(s) 1-4, 10, and 12, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither U.S. Patent No. 11,229,674 B1, Alahdal et al., nor Mellor et al. teach an immunotherapy providing one of the antigens of instant claim 5, which is anti-angiogenic or endothelial cell based.
Regarding instant claim 5, Kim et al. teaches that Pan02 tumors express VEGF; see Figure 1, for example.
Kim et al. does not anti-angiogenic or endothelial cell based effects of the Pan02 tumor lysate vaccine.
Gavilondo et al. teaches treating cancer with a therapeutic cancer vaccine comprising VEGF as an antigen with 12 of 30 patients demonstrating objective response; see Abstract, for example. Regarding instant claims 14 and 15, Gavilondo et al. teaches vaccines comprising VEGF are anti-angiogenic therapies that result in the development of polyclonal antibodies against VEGF that block its interaction with VEGFR on endothelial cells. Since the mechanism of action works, in part, by blocking signaling in endothelial cells, a vaccine comprising VEGF is endothelial cell based.
It would have been obvious to one of ordinary skill in the art that administering a Pan02 tumor lysate vaccine as taught by Alahdal et al. would comprise VEGF as one of the antigens since Kim et al. teaches that Pan02 tumors express VEGF. Gavilondo et al. teaches treating cancer with a therapeutic cancer vaccine comprising VEGF as an antigen with 12 of 30 patients demonstrating objective response, thus one of ordinary skill would have had a reasonable expectation of success treating with an anti-angiogenic immunotherapy wherein the tumor lysate vaccine comprises VEGF as an antigen.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 5, 14, 15, and 16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,229,674 B1 in view of Alahdal et al. (Scientific Reports. 8:9869; Published: June 29, 2018) as evidenced by Mellor et al. (Journal of Reproductive Immunology. 52: 5-13; Published Online: October 8, 2001) as applied to claim(s) 1-4, 10, and 12 above, and further in view of Ichim et al. (Journal of Translational Medicine. 13: 90; Published: March 14, 2015).
The teachings of U.S. Patent No. 11,229,674 B1 in view of Alahdal et al. as evidenced by Mellor et al. as related to claim(s) 1-4, 10, and 12, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither U.S. Patent No. 11,229,674 B1, Alahdal et al., nor Mellor et al. teach an immunotherapy comprising IFN-gamma pretreated placental endothelial cells.
Regarding claims 14-16, Ichim et al. teaches treating cancer with “ValloVax”, an anti-angiogenic vaccine comprising IFN-gamma pretreated placental endothelial cells; see Abstract, for example. Ichim et al. teaches that “ValloVax” resulted in a significant reduction in tumor growth and metastasis; see Abstract, for example. Regarding claim 5, Ichim et al. teaches that placental endothelial cells are used as a polyvalent antigenic source and shares the following molecules with tumor endothelial cells: VEGF, placental growth factor, angiopoietin, FGF, EGF, and TGF-beta; see paragraph bridging page 6 and 7.
Given that Alahdal et al. teaches an IDO inhibitor supports immunotherapeutic vaccines susceptibility and tumor specific targeting by reducing tumorigenic signaling pathways (see Abstract and Figure 5, for example), it would have been obvious to one of ordinary skill in the art to combine “ValloVax” taught by Ichim et al. with the IDO inhibitor, Quadramune, taught by the issued claims. One would have had a reasonable expectation of success and predictability because both “ValloVax” and the tumor lysate vaccine taught by Alahdal et al. aim to produce an immunogenic response to tumor or tumor endothelial antigens and Alahdal et al. demonstrates that the addition of an IDO inhibitor resulted in significantly decrease tumor size and increased survival.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Zheng et al. (Biomedicine & Pharmacotherapy. 90: 339-349; Published Online: April 2, 2017) teaches that metapristone, the primary metabolite of mifepristone, demonstrated dual function of anti-proliferation and anti-migration in a mouse melanoma model; see Abstract.
Bastola et al. (Cancers. 14: 2949; Published: June 15, 2022) teaches synergistic anti-cancer effects of valosin-containing protein (VCP) inhibition and mifepristone against ovarian cancer cell lines; see Figure 2, for example. However, the VCP inhibitors taught by Bastola et al. are not immunotherapies.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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