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
The Amendments and Remarks filed 16 August 2023 are acknowledged and have been entered. Claims 18-19 , 21, and 24-38 have been cancelled. Claims 1-17, 20 and 22-23 are pending and being examined on the merits.
Priority
This application is a 371 PCT of US2021/047452 filed 08/25/2021 which claims priority to application 63/070,427 filed 08/26/2020.
Information Disclosure Statement
The information disclosure statements filed 05/18/2023 have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 46. 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.
Specification
The use of the several terms including Gibco, GenScript, SpectraMax M3, to name a few, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Please thoroughly check the specification for additional marks or names.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 3 is objected to because of the following informalities: “Mesenchymal stem cell” is recited twice as an alternative. Appropriate correction is required.
Claim Interpretation
The claims are drawn to a hybrid allosteric receptor (HAR) polypeptide comprising an intracellular bone morphogenetic protein 2 type II receptor (BMP2RII) domain. A NCBI search of BMPRII did not reveal any hits; however, a google search of bone morphogenetic protein 2 type II receptor identifies the receptor as BMPR-II. Therefore, a bone morphogenetic protein 2 type II receptor (BMP2RII) domain is being interpreted as BMPR-II or BMPR-2.
Claim Rejections - 35 USC § 112
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, 20 and 22-23 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.
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, claims 1 and 20 recites the broad recitation an intracellular bone morphogenetic protein (BMP) type I receptor, and the claim also recites ALK3 which is the narrower statement of the limitation. The claim(s) are 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.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 5, 7, 12-14, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Qi (US 20170198308 A1) in view of Persson (Persson et al. The Journal of Biological Chemistry. Vol. 272, No. 34, Issue of August 22, pp. 21187–21194, 1997).
Regarding claims 1, 7, and 20, Qi teach a chimeric receptor polypeptide that comprises at least an extracellular region ( e.g., ligand binding domain) of a GPCR where the GPCR is CXCR4 [0137-0139]. Qi teaches that ligand binding can activate an associated G protein, which then functions in various signaling pathways [0136]. Qi teaches that CXCR4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF1, also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes and enhance T cell recognition of cancer microenvironment [0417]. Qi also teaches that the chimeric receptor can comprise a type I receptor such as ALK3 and a type II receptor such as BMPR2. Qi teaches that the receptor can be sequestered in a certain compartment of a cell where the cell can be a stem cell [0250, 0257]. Qi teaches nucleic acids encoding the receptors [0360].
Qi does not teach combining the CXCR4, ALK3, and BMPR2 into one molecule to create a hybrid allosteric receptor (HAR) polypeptide.
Persson teaches the generation of two different chimeric TGF-b superfamily receptors, i.e. TbR-I/BMPR-IB, containing the extracellular domain of TGF-b type I receptor (TbR-I) and the intracellular domain of bone morphogenetic protein type IB receptor (BMPR-IB), and TbR-II/ActR-IIB, containing the extracellular domain of TGF-b type II receptor (TbR-II) and the intracellular domain of activin type IIB receptor (ActR-IIB) [abstract]. Persson teaches signaling activities of chimeric human granulocyte-macrophage colony-stimulating factor receptor/ActR-II and human granulocyte-macrophage colony-stimulating factor receptor/BMPR-II [pg. 21193, col. 1, para 1].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to construct a polypeptide comprising extracellular domain of CXCR4 and the intracellular domains of BMP2RII and ALK3 for the purpose of studying BMP signaling in tumor infiltration T cells.
Regrading claim 3, Qi teaches that the stem cell can be an adult stem cells, embryonic stem cells, or iPS cells [0257].
Regarding claim 5, Qi teaches that the stem cell can be a cardiac progenitor cells (i.e., a subject-derived stem cell) [0257].
Regarding claims 12 and 13, Qi teaches that conventional viral and non-viral based gene transfer methods can be used to introduce nucleic acids in mammalian cells or target tissues where Viral vector delivery systems can include DNA and RNA viruses, which can have either episomal or integrated genomes after delivery to the cell [0360].
Regarding claim 14, Qi teaches that promoters can with the composition or chimeric receptors of the disclosure [0353; 0420].
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Qi (US 20170198308 A1) in view of Persson (Persson et al. The Journal of Biological Chemistry. Vol. 272, No. 34, Issue of August 22, pp. 21187–21194, 1997) as applied to claim 1 and further in view of Fujiwara (Fujiwara et al. Cells 2020, 9(5), 1182) and Chen (Chen et al. Adv Drug Deliv Rev. 2013 October 15; 65(10): 1357–1369).
The teachings of Qi and Persson are discussed above as applied to claim 1 and similarity apply to claim 2.
Qi and Persson do not teach where hybrid receptor further comprises a cluster of differentiation 8 alpha (CD8a) leader sequence, a CD8a hinge domain, a CD8a transmembrane domain between the CXCR domain and the BMPR2II domain, and a polyglycine linker between the BMPR2II domain and the ALK3 domain.
Fujiwara teaches chimeric antigen receptor (CAR)-T cells whose hinge or hinge/transmembrane domains originated from CD8a [abstract; Fig. 1]. Fujiwara teaches that CARs with a CD8a hinge domain (HD) caused CAR expression level to increase significantly and that CAR expression level was enhanced much more in CD8a Hinge/Transmembrane Domain (HD/TMD)-modified than in HD-modified CARs [pg. 6, last paragraph].
Chen teaches the flexible GS linker has been shown to improve folding, stability, and bioactivity in several fusion protein [pg. 8, para 4-5; see section 5.3].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the hybrid receptor as taught and suggested by Qi and Persson to comprise a cluster of differentiation 8 alpha (CD8a) leader sequence, a CD8a hinge domain, a CD8a transmembrane domain between the CXCR domain and the BMPR2II domain, and a polyglycine linker between the BMPR2II domain and the ALK3 domain. One of ordinary skill would be motivated to make the modification for the advantage of creating a hybrid receptor with improved expression, folding, stability, and bioactivity.
Claims 4, 6, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Qi (US 20170198308 A1) in view of Persson (Persson et al. The Journal of Biological Chemistry. Vol. 272, No. 34, Issue of August 22, pp. 21187–21194, 1997) as applied to claim 1 and further in view of Yan (Yan et al. Adv. Sci. 2019, 6, 1900605).
The teachings of Qi and Persson are discussed above as applied to claim 1 and similarity apply to claims 4, 6, and 15-17.
Qi and Persson do not teach where the stem cell is a mouse mesenchymal stem cell. Qi and Persson do not teach a method or means for treating myocardial infarction comprising contacting cardiovascular tissue with an effective amount of one or more of the engineered stem cells.
Yan teaches the biological engineering of the cell membrane by teaching that genetic engineering offers selective introduction of desired proteins or peptides on cell membranes through transfection or transduction via nonviral or viral vectors which is used to modify cell membranes with fused motifs for targeting and therapeutic applications [pg. 7, col. 1, para 2]. Yan teaches that Mesenchymal stem cells (MSCs) exhibit an inherent ability to home to inflammatory environment and exert immunosuppressive functions; therefore, MSCs have been genetically engineered to over-express membrane proteins such as C-X-C motif receptor 4 to enhance their homing to inflammatory environments [pg. 7, col. 1, para 2 – pg. 8, col. 2, para 1]. Qi teaches that MSCs are important immunoregulator cells in the body and in response to inflammation, MSCs express a variety of chemokine and cytokine receptors that can drive MSCs to the inflammatory sites by migrating toward inflammation and thus control inflammation locally where CXCR4/SDF-1 is a key receptor/chemokine pair [pg. 12, col. 1, para 2]. Yan teaches overexpressing homing receptors such as CXCR4 could improve MSC migratory behavior toward injured and inflamed sites and the cancer microenvironment and that CXCR4 has been widely used for enhancing homing and migration properties for myocardial infarction repair and bone related diseases [pg. 12, col. 1, para 2]. Yan teaches chemical strategies for cell membrane engineering in mice cells [Fig. 4-5 and 12].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that the cardiovascular tissue of a mouse or human engineered with mesenchymal stem cells that comprises the hybrid receptor as taught and suggested by Qi and Persson could be used in a method for treating myocardial infarction given the teachings of Yan who discloses that homing receptors such as CXCR4 has been widely used for enhancing MCS homing and migration properties for myocardial infarction repair.
Claims 9 is rejected under 35 U.S.C. 103 as being unpatentable over Qi (US 20170198308 A1) in view of Persson (Persson et al. The Journal of Biological Chemistry. Vol. 272, No. 34, Issue of August 22, pp. 21187–21194, 1997) as applied to claim 1 and further in view of Heidecke (US 20210311048 A1; filed 2/16/2017).
The teachings of Qi and Persson are discussed above as applied to claim 1 and similarity apply to claims 4, 6, and 15-17.
Qi and Persson do not teach where the CXCR domain comprises a polypeptide is at least 90% identical to SEQ ID NO: 10.
Heidecke teaches a method for diagnosis an autoimmune disease in a subject wherein, presence or absence of an anti-CXC chemokine receptor 4 (CXCR4) antibody is detected in a sample from the subject diagnosed; and teaches naturally occurring CXCR4 receptors [0114-0121]. Heidecke teaches SEQ ID NO: 6, a sequence that encodes the immunogenic CXCR4b fragment that is 100% identical to the current application’s SEQ ID NO: 1 [0082].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to substitute the CXCR4 domain in the hybrid receptor taught and suggested by Qi and Persson with the CXCR4b fragment of Heidecke. This modification would amount to a simple substitution of one known CXCR4 domain for another. One of ordinary skill would be motivated to make modification since Heidecke teaches CXCR4 protein sequences, fusion proteins, or fragments thereof.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: The prior art does not teach a sequence that is at least 90% identical to SEQ ID NOs: 1-2, and 9.
Therefore claims 8, 10-11, and 22-23 are free of the art and are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637