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 .
Application Status
Applicant’s response filed February 12, 2026, including remarks and amendments to the claims, is acknowledged. Claims 1, 12, 14, 16, 20, 32, 46, 49, and 53 were amended, and claims 5-9, and 19 were cancelled. Claims 1, 12, 14-16, 20, 22, 32-34, 37, 46, 48-49, 53, 57-59, 63-64, 73, 78, and 88 are pending.
Restriction/Election
Claims 73, 78, and 88 remain withdrawn from further consideration as being drawn to a nonelected invention, and claims 32-34, and 37 remain withdrawn as being drawn to nonelected species. Claims 1, 12, 14-16, 20, 22, 46, 48-49, 53, 57-59, and 63-64 are under examination hereinafter.
Withdrawn Rejections
Applicant’s remarks and amendments to the claims have been thoroughly reviewed. Applicant’s amendments to claim 1 to require administration of “CD34+ hematopoietic stem cells (HSCs) comprising a nucleic acid molecule that encodes NOD2, wherein the CD34+ HSCs are transduced or transfected ex vivo to expressed NOD2” is sufficient to overcome the § 102 rejections raised in the prior action over Kang, and the § 103 rejections raised in the prior action over Kang as evidenced by Orphanides, in view of López-García and Sioud. The amendments are also sufficient to overcome the § 103 rejections over Kang as evidenced by Orphanides, in view of López-García, Sioud, Mayor, and Varma, in the manner in which the rejections were applied in the prior action; the rejections relied upon administration of stem cells expressing NOD2 as evidenced by Orphanides or Sioud, rather than administration of CD34+ HSCs comprising an exogenous nucleic acid molecule sufficient to express NOD2, e.g., a viral vector or plasmid encoding NOD2. The aforementioned rejections are withdrawn, accordingly.
The remarks and amendments to the claims have been considered, but are not found persuasive to place the claims in condition in allowance for the reasons that follow. Any objection or rejection not reiterated herein has been overcome by Applicant’s response.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
In the instant case, the disclosure of the prior-filed provisional application, Application No. 62/934,345, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for instant claim 53. Application No. 62/934,345 does not disclose “an EFS promoter” as recited in instant claim 53. The first disclosure of an EFS promoter is in Application No. PCT/US2020/060288 (see pg. 13). Accordingly, the effective filing date of claim 53 is November 12, 2020. Claims 1, 12, 14-16, 20, 22, 46, 48-49, 57-59, and 63-64 find support in Application No. 62/934,345, and therefore, the effective filing date of these claims is November 12, 2019.
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 14-15, 46, and 48-49 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. The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
Claims 14, 46, and 49, recite “the composition.” No such “composition” is explicitly or implicitly provided in claim 1, from which these claims depend. There is insufficient antecedent basis for this limitation in the claims.
Claim 15, which also recites “the composition,” and claim 48, are rejected for depending from claims 14 and 46, respectively, and failing to remedy the indefiniteness. In the interest of compact prosecution, these claims will be treated hereinafter as if sufficient antecedent basis were provided in claim 1 for the term “the composition.”
Notice to Joint Inventors
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.
Claim Rejections - 35 USC § 103 – López-García in view of Mayor and Varma
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.
Claims 1, 12, 16, 20, 22, 46, 48-49, 53, 57-59, and 63-64 are rejected under 35 U.S.C. 103 as being unpatentable over López-García (López-García et al., 2017, Journal of Crohn’s and Colitis, pg. 1161-1168; of record) in view of Mayor (Mayor et al., 2012, Bone Marrow Research, Vol. 2012, Article ID 180391, pg. 1-13; of record) and Varma (Varma et al., 2011, Journal of Stem Cells & Regenerative Medicine, Vol. 7, No. 1, pg. 41-53; of record). The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
Claim 1 requires providing the patient with “CD34+ hematopoietic stem cells (HSCs) comprising a nucleic acid molecule that encodes NOD2, wherein the CD34+ HSCs are transduced or transfected ex vivo to express NOD2.” The CD34+ HSCs are a product by process (i.e., cells produced by transduction or transfection ex vivo), wherein the structure conferred by the process is CD34+ HSCs comprising an exogenous nucleic acid molecule sufficient to express NOD2, e.g., a viral vector or plasmid encoding NOD2.
Regarding claim 1, López-García teaches a method of treating Crohn’s disease in a patient in need thereof, comprising administering a composition comprising CD34+ autologous hematopoietic stem cells (hereinafter, “CD34+ AHSCs”) to Crohn’s disease patients refractory to treatment with approved medications, e.g., azathioprine, methotrexate, infliximab (“Haematopoietic stem cell transplantation [HSCT] is considered a therapeutic option for patients with severe Crohn’s disease [CD] unresponsive to currently available therapies,” Background; section 2.2, p. 1162; Table 1; section 2.4, pg. 1162; section 3.1-3.3, pg. 1163-1164). López-García teaches that transplantation with CD34+ AHSCs offers “significant and durable benefit in the majority of [] patients who were unresponsive to all available medical options,” which can “change the course of the disease by ‘allegedly resetting’ the immune system, allowing a great majority of very refractory patients [up to 80%] to regain response to conventional therapy upon relapse” (section 4, pg. 1165-1166).
López-García does not teach that the CD34+ AHSCs comprise an exogenous nucleic acid molecule sufficient to express NOD2, e.g., a viral vector encoding NOD2.
However, Mayor teaches that three polymorphisms in NOD2 – R702W, G908R, and L1007fs –increase the risk of Crohn’s disease (section 3, pg. 3-4; Fig. 1). Mayor teaches that individuals heterozygous for any of the three polymorphisms have a two- to fourfold increased risk of developing Crohn’s disease, which increases to approximately twentyfold in homozygous individuals (section 3, pg. 3-4). Mayor teaches that the polymorphisms are thought to reduce the ability of MDP to activate NOD2, and increase permeability of the gastrointestinal mucosa, both of which contribute to Crohn’s disease (section 5, pg. 3). Mayor cites a study which teaches that Crohn’s disease patients with a wildtype NOD2 genotype have a “33% rate of complete response to treatment as compared to none of the patients with NOD2 variant genotypes” (pg. 8, right col.). Mayor teaches that NOD2 is expressed in CD34+ cells (pg. 2, right col.).
Based on Mayor, the skilled artisan would have recognized that the genotype of the Crohn’s disease patients in López-García’s method, and therefore, the genotype of the transplanted CD34+ AHSCs, would impact the therapeutic success of López-García’s method. Mayor does not teach an approach to minimize the effects of the polymorphisms above in the CD34+ AHSCs isolated from patients with Crohn’s disease.
However, Varma teaches such an approach, in which CD34+ hematopoietic stem cells are transduced with a lentiviral vector comprising a transgene (“GFP”) operably linked to a ubiquitous promoter (“CMV,” “SV40,” “EF1,” etc., Fig. 1; Materials & Methods, pg. 42-43). Varma teaches that hematopoietic stem cells have “enormous potential for clinical use in cell-based therapies, especially as a gene delivery system” (Abstract, pg. 41; Discussion, pg. 49-50). Varma’s work identifies vector systems that can “generate robust foreign gene expression” in hematopoietic stem cells (Abstract, pg. 41). Specifically, Varma teaches that lentiviral vectors “are found to be [a] better gene transduction vector for hHSCs” because they “transduce non-dividing cells and produce stable expression of transgene with relatively low cytotoxicity” (pg. 49, left col.). Varma also identifies CMV and EF1 promoters are driving the highest levels of transgene expression, with the EF1 promoter being best for driving transgene expression in prolonged culture ex vivo (pg. 50-51).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have transduced the CD34+ AHSCs in López-García’s method ex vivo with a lentiviral vector encoding a NOD2 transgene operably linked to a ubiquitous or tissue-specific promoter, and administered a composition comprising the transduced cells to a Crohn’s disease patient having one or more of the three loss-of-function NOD2 mutations described by Mayor above. It would have amounted to adapting a known method for treating Crohn’s disease patients, to treat a specific population of Crohn’s disease patients with known loss-of-function mutations affecting NOD2 function, by known means, to yield predictable results.
Mayor teaches three polymorphisms in NOD2 which increase the risk of Crohn’s disease and reduce patient’s response to treatment. The skilled artisan would have expected to find these polymorphisms in Crohn’s disease patients which could benefit from López-García’s treatment method. Based on Mayor, the skilled artisan would have recognized that NOD2 polymorphisms could affect the therapeutic abilities of CD34+ AHSCs isolated from Crohn’s disease patients harboring the polymorphisms. Varma teaches an approach to provide human hematopoietic stem cells with a functional copy of NOD2, which Mayor’s teachings suggest would result in an increased response to treatment. Taken together, the skilled artisan would have been motivated to provide Crohn’s disease patients with known loss-of-function mutations affecting NOD2 function, with CD34+ AHSCs expressing functional NOD2, with a reasonable expectation of success, because López-García teaches that CD34+ AHSCs are an effective treatment for Crohn’s disease, and Mayor’s teachings suggest that NOD2 polymorphisms would affect the therapeutic abilities of CD34+ AHSCs isolated from a specific population of Crohn’s disease patients.
Regarding claims 12 and 16, the cells used in the method rendered obvious above are human CD34+ autologous hematopoietic stem cells (section 2.4, pg. 1162; sections 3.1-3.3, pgs. 1163-1164; Table 1).
Regarding claims 20 and 22, the cells used in the method rendered obvious above are transduced with a Retroviridae family virus vector which is a lentiviral vector.
Regarding claim 46, the claim is interpreted as referring to a process through which the cells administered in the method of claim 1 are prepared, i.e., they are prepared from a “precursor” population of cells, e.g., autologous cells, wherein the population is expanded ex vivo. The structure conferred to the cells used in claim 1 by the recited process of claim 46, is CD34+ AHSCs comprising an exogenous nucleic acid molecule sufficient to express NOD2. The cells in the method rendered obvious above are CD34+ AHSCs comprising an exogenous nucleic acid molecule sufficient to express NOD2.
Regarding claim 48, the term “pluripotent cell mobilization agents” is interpreted as an agent that mobilizes pluripotent cells, e.g., G-CSF (pg. 11, lines 11-26; pg. 22, lines 25-29). López-García teaches that the patient is administered one or more pluripotent cell mobilization agents (“G-CSF”), prior to isolation of cells from the patient (section 2.4, pg. 1162; section 3.2, pg. 1163; Fig. 1).
Regarding claim 49, the term “conditioning agents” is interpreted as an agent that prepares a subject for receipt of the population of cells, e.g., cyclophosphamide (pg. 17, lines 25-34; pg. 53, lines 23-30). López-García teaches that the patient is administered one or more conditioning agents (“Cyclophosphamide” or “Cy”) to ablate a population of endogenous pluripotent cells, prior to administering the composition to the patient (section 2.4, pg. 1162; section 3.3, pg. 1163-1164; Fig. 1).
Regarding claim 53, the lentiviral vector in the method rendered obvious above comprises a transgene encoding NOD2 under the control of a ubiquitous or tissue-specific promoter, e.g., a CMV or an EF1 promoter taught by Varma (Fig. 1; Materials & Methods, pg. 42-43).
Regarding claim 57, the patients in the method rendered obvious above are human patients (section 3.1, pg. 1163, left col.; Table 1).
Regarding claims 58-59, the patients in the method rendered obvious above have a loss-of-function mutation in NOD2, wherein the loss-of-function mutation is R702W, G908R, and/or L1007fs (Mayor, section 3, pg. 3-4; Fig. 1).
Regarding claims 63-64, as stated above, López-García teaches that autologous HSCT is used for patients refractory (i.e., unresponsive) to treatment with approved medications, e.g., azathioprine, methotrexate, infliximab (“Haematopoietic stem cell transplantation [HSCT] is considered a therapeutic option for patients with severe Crohn’s disease [CD] unresponsive to currently available therapies,” Background; section 2.2, p. 1162; Table 1).
Claim Rejections - 35 USC § 103 – López-García, Mayor, and Varma, in further view of Oyama
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over López-García (López-García et al., 2017, Journal of Crohn’s and Colitis, pg. 1161-1168; of record), Mayor (Mayor et al., 2012, Bone Marrow Research, Vol. 2012, Article ID 180391, pg. 1-13; of record), and Varma (Varma et al., 2011, Journal of Stem Cells & Regenerative Medicine, Vol. 7, No. 1, pg. 41-53; of record) as applied to claims 1, 12, 16, 20, 22, 46, 48-49, 53, 57-59, and 63-64 above, and in further view of Oyama (Oyama et al., 2005, Gastroenterology, 2005; 128:552-563). The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
The teachings of López-García, Mayor, and Varma are described above and applied as to claims 1, 12, 16, 20, 22, 46, 48-49, 53, 57-59, and 63-64 hereinafter.
None of López-García, Mayor, or Varma teach intravenously injecting the CD34+ AHSCs into the patient.
However, Oyama teaches a substantially identical method to López-García (“Autologous Hematopoietic Stem Cell Transplantation in Patients with Refractory Crohn’s Disease”), in which autologous hematopoietic stem cells are intravenously injected into a patient (“patients.. underwent T cell-depleted (CD34+ cell-enriched) HSCT,” pg. 553, left col.; “HSCs were infused intravenously on day 0…,” pg. 553, right col.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have intravenously injected the CD34+ AHSCs used in the method rendered obvious above in view of Oyama. It would have amounted to administering CD34+ AHSCs to a patient in an obvious method of treatment, by known means to yield predictable. The skilled artisan would have been motivated to intravenously inject the autologous CD34+ hematopoietic stem cells, with a reasonable expectation of success, because López-García is silent as to the specific injection route through which the cells are administered, and Oyama teaches that intravenous injection is a suitable means to administer autologous hematopoietic stem cells to Crohn’s disease patients.
Response to Remarks - 35 USC § 103
Applicant’s remarks regarding the § 103 rejections raised in the prior action have been reviewed. Applicant’s remarks are moot because the new grounds of rejection do not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the remarks.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNA L PERSONS whose telephone number is (703)756-1334. The examiner can normally be reached M-F: 9-5pm.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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