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 .
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.
This office action is a response to applicant’s communication submitted June 2, 2023, wherein claims 5-8, 12-13, 19-20, and 25-26 were preliminarily amended, and claims 27-29 were canceled.
Claims 1-2, 5-14 and 19-26 are pending in this application.
Priority
This application is a 371 of PCT/US2021/061619 filed December 2, 2021 and claims the benefit of US provisional application 63/121,133 December 3, 2020. However, the provisional application does not provide written description for the present claims under 35 USC 112(a). In particular, the provisional application only provides support for a few specific compounds and not the broad genus as instantly claimed. The provisional application provides support for tunicamycin, thapsigargin, and IXA4 (claim 7), and CPI-613 (which corresponds to the specific compound recited by instant claims 10-11). The support for the entire genus recited by the remaining claims is first found in the PCT application. Thus 1-2, 5-6, 8-9, 12-14 and 19-26 have an effective filing date of the PCT application, filed December 2, 2021, while claims 7 and 10-11 have an effective filing date of December 3, 2020.
Specification
The disclosure is objected to because of the following informalities: Structures of Table 1 on pages 14-15 are blurry, rendering them unclear, particularly the structures of Tunicamycin and Thapsigargin.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (pg. 43, references 45, 48, and 50). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Objections
Claim 20 is objected to because of the following informalities:
Claim 20 recites “TNF-a” which should read “TNF-α“. Appropriate correction is required.
Claim Rejections - 35 USC § 112 (a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5-6, 12-14, 19-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims require “a compound that activates the Unfolded protein response (UPR) in immune cells” or “a compound that disrupts the tri-carboxylic acid (TCA) cycle in immune cycles”. The claims do not require that the compounds that activate UPR or disrupt the TCA cycle possess any particular conserved structure, or other distinguishing feature. Thus, the claims are drawn to a genus of compounds that is defined by novelty.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997) (patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”); In re Gosteli, 872 F.2d 1008, 1012 [10 USPQ2d 1614] (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”). Thus, an applicant complies with the written-description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572.
According to the MPEP §2163 I. A. “the issue of a lack of adequate written description may arise even for an original claim when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the applicant had possession of the claimed invention. The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.” The MPEP states in §2163 II 3 ii) “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A), above), reduction to drawings (see i)(B), above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.”
According to the MPEP §2163.02 Standard for Determining Compliance With the Written Description Requirement,
“The courts have described the essential question to be addressed in a description requirement issue in a variety of ways. An objective standard for determining compliance with the written description requirement is, “does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed". In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed. The test for sufficiency of support in a parent application is whether the disclosure of the application relied upon “reasonably conveys to the artisan that the inventor had possession at that time of the later claimed subject matter". Ralston Purina Co. v. Far-Mar-Co., Inc., 772 F.2d 1570, 1575, 227 USPQ 177, 179 (Fed. Cir. 1985) (quoting In re Kaslow, 707 F.2d 1366, 1375, 217 USPQ 1089, 1096 (Fed. Cir. 1983)).”
This case was filed before Applicants had a clear idea of the structures of their desired compounds, how to make their compounds and how to use them.
Applicants are reminded of what the U.S. Court of Appeals Federal Circuit wrote in University of California v. Eli Lilly and Co. 43 USPQ2d 1398, "In claims involving chemical materials, generic formulae usually indicate with specificity what the generic claims encompass. One skilled in the art can distinguish such a formula from others and can identify many of the species that the claims encompass. Accordingly, such a formula is normally an adequate description of the claimed genus." "A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is.” See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). "It is only a definition of a useful result rather than a definition of what achieves that result." "The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.")".
Therefore, the full breadth of the claim fails to meet the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision
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 10 and 24 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.
Regarding claim 10: Claim 10, which depends from claim 7, recites inter alia, “wherein the compound of formula I is….”. However, claim 7 does not recite compounds of Formula I. Thus, there is a lack of antecedent basis for this phrase, rendering the claim indefinite. The Examiner makes note that claims 10-11 appear to refer to the same compound, thus amending claim 10 such that it depends on claim 8 would result in a duplicate claim.
Regarding claim 24: A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 24 recites the broad recitation “at least 20%” and the claim also recites “at least 25%, at least 30%, at least 35%...etc.” which are the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 102
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.
Claims 2, 8-9, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shorr (US 20100190858, IDS filed February 1, 2024).
Regarding claims 2, 8-9, and 11: Shorr teaches methods of treating disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation comprising 6,8-bis(benzylthio)octanoic acid (pg. 15, para. 0109, 0113). Shorr teaches this compound is also known as CPI-613, pg. 18, para. 0145). The lipoic acid derivates are capable of inhibiting PDC activity, which is a larger multi-subunit complex involved in producing acetyl CoA (pg. 15, para. 0110, pg. 1, para. 0003). Acetyl CoA effectively funnels glycolysis-produced pyruvate to the TCA cycle (pg. 1, para. 0003). Thus, wherein the compound inhibits PDC activity, it necessarily disrupts the TCA cycle. Shorr teaches diseases to be treated include psoriasis (pg. 15, para. 0114).
Claims 2 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kroemer (WO 2015/049365, IDS filed February 1, 2024).
Regarding claims 2 and 8: Kroemer teaches methods for the modulation of autophagy and the treatment of autophagy related disease (abstract). Kroemer teaches autophagy is associated with autoimmune diseases (pg. 1, lines 12-20, pg. 20, lines 19-33, pg. 21, lines 1-5). Kroemer teaches a compound of the invention includes UK5099, which is an inhibitor of the mitochondrial pyruvate carrier complex (pg. 5, lines 8-10). Kroemer teaches UK5099 inhibits pyruvate transport from cytoplasm to mitochondria (pg. 28, lines 7-10). The instant specification refers to UK5099 as a TCA inhibitor (pg. 38, lines 6-16). Thus, UK5099 necessarily inhibits the TCA cycle. Kroemer teaches autoimmune diseases include psoriasis (pg. 21, lines 1-20).
Claims 1, 5-7, 12, 19-24, and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nakajima (US 2007/0244060, cited on PTO-892) as evidenced by Ye (Clinical & Translational Immunology, 2020, IDS filed February 1, 2024).
Regarding claims 1, 7, 12: Nakajima teaches a therapeutic agent for autoimmune diseases, comprising a substance that induces ER stress (abstract). Nakajima teaches that agent that is capable of inducing endoplasmic reticulum stress includes tunicamycin and thapsigargin (pg. 1, para. 0014). Nakajima teaches rheumatoid arthritis is an example of a target for the therapeutic agent of the invention (pg. 1, para. 0016). Nakajima teaches the method includes administration to a subject for treatment of such disease (pg. 3, para. 0046). Nakajima teaches other diseases to be treated include systemic lupus erythematosus, multiple sclerosis and Sjogren’s syndrome (pg. 3, para. 0046). Nakajima teaches that inducing ER stress results in activation of UPR that degrades unfolded protein (pg. 1, para. 0007).
Regarding claims 6, and 19-23: According to Ye, plasmacytoid dendritic cells (pDCs) are a unique subset of dendritic cells specialized in secreting high levels of type I interferons and have been implicated in the initiation and development of many autoimmune and inflammatory diseases (abstract). Ye teaches pDCs are implicated in systemic lupus erythematosus (SLE, pg. 2, col. 1, para. 1).Human pDCs were traditionally defined as not expressing the lineage-associated markers (Lin) CD3, CD19, CD14, CD16 and CD11c, but selectively expressing CD303 (BDCA2), CD304 (BDCA4) and immunoglobulin-like transcript 7 (ILT7) (pg. 2, col. 1, para. 3). Wherein Ye establishes that these dendritic cells are present in autoimmune diseases such as SLE, and Nakajima teaches inducing ER stress that activates UPR via tunicamycin, the claimed properties associated with plasmacytoid dendritic cells are an inherent property of practicing the method, absent evidence to the contrary. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer (See MPEP 2112 (I)).
Regarding claim 5: According to the instant specification, treatment of pDC with tunicamycin activates the IRE1a-XBP1 signaling branch of the UPR in immune cells (pg. 10, lines 18-25, drawings, figures 6A-6B). Thus, wherein the prior art teaches administration of tunicamycin for the treatment of autoimmune diseases, this is an inherent property of the method. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer (See MPEP 2112 (I)).
Regarding claim 24: According to the instant specification, the IRE1a-XBP1 branch inhibits the production of IFN-I (pg. 12, lines 25-28). Thus, wherein the prior art teaches administration of tunicamycin for the treatment of autoimmune diseases, and tunicamycin necessarily activates the IRE1A-XBP1 branch, this is an inherent property of the method. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer (See MPEP 2112 (I)).
Regarding claim 26: According to the instant specification, treatment of pDC cells with tunicamycin enhances the expression of PHGDH (pg. 7, lines 21-29, Drawings, figures 2D-2F). Thus, whereas Nakajima teaches tunicamycin for the treatment of autoimmune diseases, necessarily result in enhancing such expression. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer (See MPEP 2112 (I)).
Claim Rejections - 35 USC § 103
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.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Nakajima (US 2007/0244060, cited on PTO-892) and Ye (Clinical & Translational Immunology, 2020, IDS filed February 1, 2024) as applied to claims 1, 5-7, 12, 19-26 above.
Regarding claim 12: Although Nakajima is cited to anticipate the method of claim 12 for the treatment of a specific autoimmune disease, such as systemic lupus erythematosus or rheumatoid arthritis, even if assuming for the sake of argument Nakajima did not explicitly teach said treatment, the claim would have been rendered obvious over Nakajima. As discussed above, Nakajima teaches a therapeutic agent for autoimmune diseases, comprising a substance that induces ER stress (abstract). Nakajima teaches that agent that is capable of inducing endoplasmic reticulum stress includes tunicamycin and thapsigargin (pg. 1, para. 0014). Nakajima teaches Rheumatoid arthritis is an example of a target for the therapeutic agent of the invention (pg. 1, para. 0016). Nakajima teaches the method includes administration to a subject for treatment of such disease (pg. 3, para. 0046). Nakajima teaches other diseases to be treated include systemic lupus erythematosus, multiple sclerosis and Sjogren’s syndrome (pg. 3, para. 0046). Nakajima teaches that inducing ER stress results in activation of UPR that degrades unfolded protein (pg. 1, para. 0007).
Taken together, It would have been prima facie obvious to a person of ordinary skill in the art to apply the treatment to systemic lupus erythematosus or rheumatoid arthritis as it is directly suggested by Nakajima to be treatable with the taught ER stress-inducing compounds. A person of ordinary skill in the art would have had a reasonable expectation of success in doing so given the disclosure suggests these compounds are beneficial in autoimmune diseases generally and directly names these individual diseases.
Claims 10 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Nakajima (US 2007/0244060, cited on PTO-892) and Ye (Clinical & Translational Immunology, 2020, IDS filed February 1, 2024) as applied to claims 1, 5-7, 12, 19-26 above, in view of Shorr (US 20100190858, IDS filed February 1, 2024).
Regarding claim 10: As discussed above, Nakajima teaches the method of claim 7. Nakajima further teaches the therapeutic ER stress inducing substances can be useful for the treatment of autoimmune diseases such as diabetes. Nakajima does not teach the administration of 6,8-bis(benzylthio)octanoic acid as recited by instant claim 10.
However, Shorr teaches methods of treating disease characterized by disease cells that are sensitive to lipoic acid derivatives comprising administering to a patient in need thereof a pharmaceutical formulation comprising 6,8-bis(benzylthio)octanoic acid (pg. 15, para. 0109, 0113). Shorr teaches this compound is also known as CPI-613, pg. 18, para. 0145). The lipoic acid derivates are capable of inhibiting PDC activity, which is a larger multi-subunit complex involved in producing acetyl CoA (pg. 15, para. 0110, pg. 1, para. 0003). Acetyl CoA effectively funnels glycolysis-produced pyruvate to the TCA cycle (pg. 1, para. 0003). Thus, wherein the compound inhibits PDC activity, it necessarily disrupts the TCA cycle. Shorr teaches diseases to be treated include diabetic neuropathy (pg. 15, para. 0114).
Taken together it would have been prima facie obvious to modify the method of Nakajima directed to treating diabetes by including a treatment with 6,8-bis(benzylthio)octanoic acid for diabetic neuropathic symptoms as taught by Shorr. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as both compounds are useful for the treatment of diabetes/diabetes related symptoms, in order to treat the underlying condition as well as associated symptoms, such as neuropathy.
Regarding claim 25: As discussed above, the prior art render obvious a method comprising administering tunicamycin and/or thapsigargin and 6,8-bis(benzylthio)octanoic acid (CPI-613). They do not disclose wherein the treatment reduces the expression of one or more of the interferon stimulated genes selected from the group consisting of GBP1, IRF7, ISG54, MxB, and/or OAS2. However, according to the instant specification, the reduction of these genes can be accomplished CPI-613, which is identical to the compound disclosed in the prior art (See instant specification, pg. 36, lines 6-14, lines 6-14). Thus, wherein it would have been obvious to administer CPI-613 through the teachings of Nakajima and Shorr, this result flows naturally as a result of practicing the method, as a compounds properties cannot be separated from the compound itself, absent evidence to the contrary.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Nakajima (US 2007/0244060, cited on PTO-892) and Ye (Clinical & Translational Immunology, 2020, IDS filed February 1, 2024) as applied to claims 1, 5-7, 12, 19-26 above, in view of Wells (Cochrane Database of Systematic Reviews, 1998, cited on PTO-892).
Regarding claims 13-14: As discussed above, Nakajima teaches a method of treating Rheumatoid arthritis with tunicamycin. Nakajima does not teach wherein the subject is concurrently treated with the immunosuppressant cyclosporin.
However, Wells teaches cyclosporin is a known treatment for Rheumatoid arthritis in reducing pain (pg. 4, para. 1).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the method, such that the method of Nakajima is administered alongside cyclosporin as taught by Wells. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success in order to more efficiently treat the condition by targeting different pathways, and both compounds are known to be effective in treating this disease.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 5:00 PM.
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/S.L.G./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693