DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 22-25, in the reply filed on 9/17/2025 is acknowledged.
Upon examination of the elected claims, claims 1-3, 5, 7-11, 16, 20 and 21 have been considered drawn to the elected subject matter. Therefore, the restriction requirement between Group I, directed to the chimeric receptor, and Group II, the cell comprising the chimeric receptor is withdrawn.
Applicant also elected SEQ ID NO: 5 as the species for the exodomains recited in claims 7-9. Since this species is recited in species claim 8, claims 7 and 9 reciting other non-elected species are withdrawn.
Applicant also elected SEQ ID NO: 44 as the species for chimeric receptor sequence recited in claims 16(iv) and optionally in claim 21.
Claims status
Claims 1-3, 5, 7-11, 16, 20-25, 33-36 is/are currently pending with claims 7, 9, 33-36 is/are withdrawn. Claims 1-3, 5, 8, 10, 11, 16, 20-25 is/are under examination.
Claim suggestion
Claim 5 recites “ADAM (a disintegrin and metalloproteinase)”. Conventionally, abbreviation of a given term/phrase follows the term/phrase. Therefore, it is recommended that claim 5 recite “A disintegrin and metalloproteinase (ADAM)”.
Claim 1 recites the abbreviation “TREM2” without its full-form. Although TREM2 is a well-known protein, recitation of the full form in the claim is recommended.
Claim Objections
Claim 3, 5, 10, 16 are objected to because of the following informalities: The periods after the letters denoting the options need to be replaced with a parenthesis. For example, in claim 3 "i." should be corrected to "i)" in line 3. MPEP 608.01(m) requires that “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995)”. In other words, a claim should only contain one period.
Claim 16 (iv) is objected to because of the following informalities: The claim is missing the word “sequence” after the phrase “an amino acid” in the second to last line. Following correction is recommended: “or an amino acid sequence having at least 90%”.
Appropriate corrections are required.
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 16, 22-25 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 16(iv), the abbreviated phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Furthermore, recitation of this limitation within brackets renders it indefinite because it is not clear if the limitation is required or optional. For the purpose of compact prosecution, the limitation within brackets in claim(s) 16(iv) is/are interpreted as an optional limitation.
Regarding claim 22, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear if the recited cell is limited to an immune cell or if the claim embraces a broader scope i.e. any cell type. For the purpose of compact prosecution, the preferred limitation in claim(s) 22 is/are interpreted as optional.
Claims 23-25 is/are rejected due their dependence on claim 22 because they do not clarify the 112b issue noted with claim 22.
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 8 and 16 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.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claim 8 recites a chimeric receptor wherein the exodomain comprises or consists of “an amino acid sequence as set forth in SEQ ID NO:5” (emphasis added). Claim 8 depends from claim 1 and thus requires the exodomain to comprise the ligand binding domain of TREM2.
The broadest reasonable interpretation of the phrase “an […] sequence […] in” embraces fragments comprised within the recited SEQ IDs. Therefore, the claim embraces exodomains that are any fragment of the SEQ ID No. 5. The specification discloses SEQ ID No: 5 as the ligand binding domain of TREM2. The specification does not disclose any fragment of TREM2 ligand binding domain or any fragment of SEQ ID No. 5 which could function as a TREM2 ligand binding domain. The fragments of SEQ ID NO: 5 can vary substantially. There is no teaching in the specification in which a fragment of SEQ ID No. 5 retains the ability of the sequence to function as a TREM2 ligand binding domain. Consequently, there is no information about which amino acids or amino acid sequences can be removed from SEQ ID NOs: 5 such that the fragment retains the required function.
Similar issue is present for claim 16.
Claim 16 recites the chimeric receptor comprises “an amino acid sequence of any one of SEQ ID NOs: 32, 33 or 40-56”
The broadest reasonable interpretation of the phrase “an […] sequence [..] of” embraces fragments comprised within the recited SEQ IDs.
Therefore, the claim embraces chimeric receptors that are any fragment of the SEQ ID NOs: 32, 33 or 40-56. The specification discloses SEQ ID No: 32, 33 or 40-56 as chimeric receptors comprising various combinations of exodomains, transmembrane domains and intracellular signaling domains. The specification does not disclose any fragment of any of the required domains, the specification does not disclose any fragment of the exodomains, the transmembrane domains and the intracellular signaling domains which retain the function of these domains. The specification does not disclose any fragment of SEQ ID NOs: 32, 33 or 40-56 which could function as the entire chimeric receptor. Furthermore, fragments of any one of SEQ ID NO: 32, 33 or 40-56 can vary substantially. There is no information about which amino acids or amino acid sequences can be removed from SEQ ID NOs: 32, 33 or 40-56 such that the fragment retains the required function.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by “whatever characteristics sufficiently distinguish it).
Further, the breadth of the genus of fragments of SEQ ID NOs: 5, 32, 33 or 40-56 lack a written description.
According to the MPEP § 2163, “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. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
In the instant case, the only factor present in the claims is a reference to structure in the form of a recitation of a SEQ ID. There is no identification of any particular portion of the structure that must be conserved. It is not clear what region of the sequence has the activity clearly associated with SEQ ID NOs: 5, 32, 33 or 40-56. The specification does not provide a complete structure of those fragments of SEQ ID NOs: 5, 32, 33 or 40-56 and fails to provide a representative number of species for the encompassed genus of fragments. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the recited genus.
Therefore, the claimed invention, as a whole, is not adequately described. The claims require essential or critical elements which are not adequately described in the specification, and are not conventional in the art before the effective filing date.
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.
Claim(s) 1, 3, 10, 11, 16, 20-25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rosenthal (US 2018/0186855 A1, Jul. 5, 2018; IDS 3/13/2023).
Regarding claim 1, Rosenthal discloses A chimeric receptor comprising an exodomain, a transmembrane domain and an intracellular signaling domain ([0008, 0083, 0085, 0088]). Rosenthal discloses exodomain comprising TREM2 ligand binding domain ([0090]).
Regarding claim 3(i), Rosenthal discloses chimeric receptors that comprise a single polypeptide chain [0085].
Regarding claim 3(ii), Rosenthal also discloses chimeric receptors that comprise two or more polypeptide chains, wherein one of the chains comprises linked domains from two or more proteins, for example an intracellular signaling domain comprises a stimulatory molecule and also a co-stimulatory molecule [0085, 0086]. In the two chain chimeric receptor, Rosenthal discloses use of linkers between various domains such as transmembrane domain and intracellular signaling domain [0086].
Regarding claim 10(i), Rosenthal discloses chimeric receptors comprising hinge domain between exodomain and transmembrane domain ([0017, 0111).
Regarding claim 10(ii), Rosenthal also discloses chimeric receptors comprising a signal sequence upstream of the exodomain (page2, col. 2 lines12-16; [0017, 0086, 0111]; claim 20).
Regarding claim 10(iii), Rosenthal also discloses chimeric receptors comprising co-stimulatory domains ([0085, 103, 106).
Regarding claim 11(i), Rosenthal discloses hinge domain from CD8 ([0017, 0111]).
Regarding claim 11(ii), Rosenthal also discloses the signal sequence of CD8 (page2, col. 2 lines12-16; [0017, 0086, 0111]; claim 20).
Regarding claim 11(iii), Rosenthal also discloses following co-stimulatory domains: CD27, CD28, 4-IBB (CD137), OX40 (CD134), CD30, CD40, ICOS (CD278), LFA-1, CD2, CD7, LIGHT ([0085, 103, 106]).
Regarding claim 16(i), Rosenthal discloses transmembrane domains is from a protein selected from a receptor tyrosine kinase (RTK), an M-CSF receptor, CSF-1R, Kit, TIE3, an ITAM-containing protein, DAP12, DAP10, an Fc receptor, FcR-gamma, FcR-epsilon, FcR-beta, TCR-zeta, CD3-gamma, CD3-delta, CD3- epsilon, CD3-zeta, CD3-eta, CD5, CD22, CD79a, CD79b, CD66d, TNF-alpha, NF-kappaB, a TLR (toll-like receptor), TLR5, Myd88, lymphocyte receptor chain, IL-2 receptor, IgE, IgG, CD16a, FcyRIII, FcyRII, CD28, 4-1BB, CD4, CD8 (page2,col.1, lines9-25; [0097,0111]).
Regarding claim 16(ii), Rosenthal discloses the intracellular signaling domain from a protein selected from a receptor tyrosine kinase (RTK), an M-CSF receptor, CSF-1R, Kit, TIE3, an ITAM-containing protein, DAP12, DAP10, an Fc receptor, FcR-gamma, FcR-epsilon, FcR-beta, TCR-zeta, CD3-gamma, CD3-delta, CD3-epsilon, CD3-zeta, CD3-eta, CD5, CD22, CD79a, CD79b, CD66d, TNF-alpha, NF-KappaB, a TLR (toll-like receptor), TLR5, Myd88, TOR/CD3 complex, lymphocyte receptor chain, IL-2 receptor, IgE, IgG, CD16a, FcyRIII, FcyCD28, 4-1BB, and any combination thereof (page2,col.1, lines25-60; [104]).
Regarding claims 20 and 21, Rosenthal discloses vectors comprising nucleic acids encoding the chimeric receptor ([0010, 0011]).
Regarding claim 22-24, Rosenthal discloses cells comprising vectors encoding the chimeric receptor, wherein the cells are an immune cell population such as NK cell, a dendritic cell, a NKT cell, a neutrophil, a macrophage or a T cell, such as a cytotoxic T lymphocyte (CTL), helper T cell or a Treg cell ([0013-0016, 0018, 0023, 0232]).
Regarding claim 25, Rosenthal discloses pharmaceutical composition comprising the cell expressing the chimeric receptor ([0021, 0262]).
Therefore, Rosenthal anticipates the claimed invention.
Claim(s) 1, 2, 3, 5, 8, 10, 11, 16, 20-22, 24 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kleinberger et al (Sci. Transl. Med. 6, 243ra86 (2014); IDS 3/13/2023) as evidenced by Hamerman et al (The Journal of Immunology, 2006, 177: 2051–2055) and NP_001258750.1 (TREM2 protein sequence, available since at least 1993).
Regarding claim 1, Kleinberger discloses a chimeric receptor comprising a TREM2 exodomain, a transmembrane domain and an intracellular signaling domain (Figure 1, 6).
Regarding claim 2, 5, Kleinberger discloses a ADAM10-sheddase resistant TREM2 exodomain due to the presence of T66M and Y38C point mutations in the exodomain (Figure 2C, 4, 6).
Regarding claim 3, Kleinberger teaches the chimeric receptor as a single polypeptide (Figure 1, 6).
Regarding claim 8, Kleinberger discloses a chimeric receptor comprising a wild type TREM2 exodomain (Figure 6). Kleinberger references Hamerman as the source of the chimeric receptor in Materials and Methods: Phagocytosis assay. Haberman evidences that the TREM2-DAP12 chimeric receptor comprises extracellular domain of wild type TREM2 protein (amino acids residues 1-169; Materials and Methods: Retrovirus). Published sequence for TREM2 (NP_001258750.1) evidences that TREM2 extracellular domain from residue 19-138 is 100% identical to SEQ ID NO: 5 (see Sequence alignment below).
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Regarding claims 10(i), 11(ii), Kleinberger’s chimeric receptor comprises a CD8 signal sequences as evidenced by Hamerman (Materials and Methods: Retrovirus).
Regarding claim 16(i), Kleinberger chimeric receptor comprises TREM2 transmembrane domain (Figure 1).
Regarding claim 16(ii), Kleinberger chimeric receptor comprises DAP12 intracellular domain (Figure 6).
Regarding claim 20, 21, Kleinberger discloses constructs i.e. vectors or nucleic acids encoding the chimeric receptors (Materials and Methods: Phagocytosis assay).
Regarding claim 22, 24, Kleinberger discloses HEK cells, BV2 cells and primary microglial cells expressing chimeric receptors (Figure 1, 4, 6).
Therefore, Kleinberger anticipates the claimed invention.
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.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal.
The teachings of Rosenthal as applied to claims 1 and 16(i), (ii) above are pertinent to the instant rejection.
Regarding claim 16(iii), Rosenthal teaches the chimeric receptor with an exodomain comprising the ligand binding domain of TREM2 ([0090]). Rosenthal provides teachings regarding the various components and designs for a chimeric receptor [0085-0111, 206]. Rosenthal teaches the use of signal peptides upstream of the N-terminus of the chimeric receptor, including signal peptide from CD8 (page2, col. 2 lines12-16; [0017, 0086, 0111]; claim 20). Rosenthal also teaches hinge domains between exodomains and transmembrane domains [0017, 0111]. Rosenthal also teaches multi-component intracellular signaling domain comprising intracellular signaling domain that could be CD3zeta and co-stimulatory domain that could be from CD28 ([0085, 103, 106], page2,col.1, lines25-60; [104]).
Take together, Rosenthal provides teachings regarding each of the components of the chimeric receptor of claim 16(iii). Furthermore, Rosenthal teaches 21 combinations of the components taught (SMART1-21 in Example 1) .
The prior art cited above under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S., 82 USPQ2d 1385 (2007). Guidance regarding exemplary rationales that may support a conclusion of obviousness include is from MPEP 2143.
In the present situation, rationale A is applicable. MPEP 2143 guides that for rationale A - Combining prior art elements according to known methods to yield predictable results; “Office personnel must articulate the following: (1) a finding that the prior art included each element claimed, although not necessarily in a single prior art reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference; (2) a finding that one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately; (3) a finding that one of ordinary skill in the art would have recognized that the results of the combination were predictable; and (4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.”.
(1) The prior art of Rosenthal teaches each of the claimed chimeric receptor components; albeit Rosenthal does not explicitly teach combining the claimed components in one chimeric receptor. (2) Rosenthal provides teachings regarding the chimeric receptor components and shows the modularity of these components by providing 21 combinations of these combination. Thus, an ordinary artisan would use the methods taught by Rosenthal to combine the chimeric receptor components wherein each component would perform the expected function. (3). The combination of the various chimeric receptor component would predictably yield a receptor that is a chimera combining components from distinct molecules as claimed.
Therefore, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR. Therefore, it would be obvious to a person of ordinary skill in the art to combine the elements taught by Rosenthal to yield a predictable result of a chimeric receptor with a combination of components taught by Rosenthal.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 2, 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal as applied to claim 1 above, and further in view of Kleinberger et al (Sci. Transl. Med. 6, 243ra86 (2014); IDS 3/13/2023).
The teachings of Rosenthal and Kleinberger as applied to claim 1 in their respective U.S.C. 102 rejections above are pertinent to the instant rejection.
Both Rosenthal and Kleinberger disclose exodomains comprising TREM2 ligand binding domain ([0090] in Rosenthal and Figure 1, 6 in Kleinberger).
Rosenthal does not teach a sheddase resistant exodomain (as recited in claim 2) wherein the sheddase is ADAM 10 or ADAM17 (as recited in claim 3).
Kleinberger teaches a ADAM10-sheddase resistant TREM2 exodomain due to the presence of T66M and Y38C point mutations in the exodomain (Figure 2C, 4, 6).
The prior art cited above under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S., 82 USPQ2d 1385 (2007). Guidance regarding exemplary rationales that may support a conclusion of obviousness include is from MPEP 2143.
In the present situation, rationale B is applicable. MPEP 2143 guides that for rationale B - Simple Substitution of One Known Element for Another To Obtain Predictable Results; “Office personnel must articulate the following: (1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components; (2) a finding that the substituted components and their functions were known in the art; (3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and (4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.”.
(1) The prior art of Rosenthal teaches the chimeric receptor with a TREM2 ligand binding domain. It differs from the claimed chimeric receptor by the substitution of a sheddase resistant TREM2 ligand binding domain, as required for claims 2, 3. (2) Kleinberger teaches a ADAM10-sheddase resistant TREM2 ligand binding domain. Kleinberger also teaches two chimeric receptor combinations comprising the wild type or the sheddase resistant TREM2 ligand binding domain (Figure 1, 2 and 6). Thus, an ordinary artisan recognized the function of the wild type and the sheddase resistant TREM2 ligand binding domain. (3) Rosenthal provides teachings regarding various chimeric receptor components and shows the modularity of these components by providing 21 combinations of these combination. Thus, an ordinary artisan recognizes the modularity of chimeric receptor components. An ordinary artisan substitute the TREM2 ligand binding domain of Rosenthal with the sheddase resistant TREM2 ligand binding domain of Kleinberger using routine methods to produce a predictable chimeric receptor that comprises a sheddase resistant TREM2 ligand binding domain.
Therefore, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR. Therefore, it would be obvious to a person of ordinary skill in the art to substitute the TREM2 ligand binding domain of Rosenthal with the sheddase resistant TREM2 ligand binding domain of Kleinberger to yield a predictable result of a chimeric receptor with a sheddase resistant TREM2 ligand binding domain.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal as applied to claim 1 above, and NP_001258750.1 (TREM2 protein sequence, available since at least 1993).
The teachings of Rosenthal as applied to claim 1 above are pertinent to the instant rejection.
Rosenthal discloses exodomains comprising TREM2 ligand binding domain ([0090] in Rosenthal).
Rosenthal does not provide the sequence for the TREM2 exodomain (as recited in claim 8).
NP_001258750.1 teaches the sequence for the TREM2 extracellular domain which comprises a sequence that is 100% identical to SEQ ID NO: 5 (see Sequence alignment above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the sequence of TREM2 exodomain known in the art, as taught by NP_001258750.1, in the chimeric receptor of Rosenthal. An ordinary artisan would be motivated to use the sequence of TREM2 taught by NP_001258750.1 because although Rosenthal teaches a chimeric receptor with TREM2 ligand binding domain, Rosenthal does not explicitly provide this sequence. An ordinary artisan would reasonably expect to use the sequence of TREM2 taught by NP_001258750.1 in the chimeric receptor of Rosenthal because NP_001258750.1 provides this sequence and Rosenthal teaches methods to generate chimeric receptors using various sequences (Example 1: Assembly, Production, Identification, and Characterization of SMART Vectors; [203]).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal as applied to claim 1 above, and NP_001258750.1 (TREM2 protein sequence, available since at least 1993) and Maher et al (WO 2021/038036 A1, Effective filing date August 28, 2019).
Regarding claim 16(iv), Elected species of SEQ ID No. 44 is allowable. See detail in the allowable subject matter below. Thus, the instant rejection is directed towards the first named species i.e. SEQ ID No: 32.
The teachings of Rosenthal as applied to claim 1 above are pertinent to the instant rejection.
Regarding claim 16(iv), Rosenthal discloses chimeric receptors with exodomains comprising TREM2 ligand binding domain ([0090] in Rosenthal).
Rosenthal does not teach the sequence for the chimeric receptor that is the same as SEQ ID NO: 32 or is at least 90% identical to SEQ ID NO: 32.
However, SEQ ID NO: 32 is a chimeric receptor comprising CD8 alpha signal peptide (aa 1-21), TREM2 ligand binding domain (aa 22-141, =SEQ ID NO: 5), CD28 spacer and transmembrane domain (aa 142-252), and CD3 zeta endodomain (aa 253-364).
Rosenthal teaches each of these components as parts of chimeric receptor.
Rosenthal teaches a CD8 signal peptide (page2, col. 2 lines12-16; [0017, 0086, 0111]; claim 20). Rosenthal teaches a TREM2 ligand binding domain (0090). Rosenthal teaches a CD28 transmembrane domain (page2,col.1, lines9-25; [0097,0111]). Rosenthal teaches CD3zeta costimulatory domain (page2,col.1, lines25-60; [104]).
Rosenthal does not provide the sequences for each of these components or provide a single sequence with each of these components together.
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NP_001258750.1 teaches the sequence for the TREM2 extracellular domain which comprises a sequence that is 100% identical to SEQ ID NO: 5 which is 100% identical aa22-141 of SEQ ID NO: 32 (see Sequence alignment below).
Maher teaches a chimeric receptor that comprises CD8 alpha signal peptide (aa 1-21), CD28 spacer and transmembrane domain (aa 142-252), and CD3 zeta endodomain (aa 253-364) (see alignment with Maher’s SEQ ID NO: 62 below). Same as Rosenthal, Maher also teaches the various chimeric receptor components and also provide separate sequences for these components (sequences listed in Table on page 51-85). Maher teaches SEQ ID NO: 1 and 2 as the sequence for CD3 zeta, SEQ ID NO: 3, 4 and 6 as sequence for CD28. The only difference between Maher’s chimeric receptor of SEQ ID NO: 62 as compared to the claimed sequence is the exodomain sequence. However, as noted above, the sequence for the TREM2
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exodomain was taught by NP_001258750.1.
The prior art cited above under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S., 82 USPQ2d 1385 (2007). Guidance regarding exemplary rationales that may support a conclusion of obviousness include is from MPEP 2143.
In the present situation, rationale A is applicable. MPEP 2143 guides that for rationale A - Combining prior art elements according to known methods to yield predictable results; “Office personnel must articulate the following: (1) a finding that the prior art included each element claimed, although not necessarily in a single prior art reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference; (2) a finding that one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately; (3) a finding that one of ordinary skill in the art would have recognized that the results of the combination were predictable; and (4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.”.
(1) The prior art of Rosenthal teaches each of the claimed chimeric receptor components i.e. CD8 alpha signal peptide, TREM2 ligand binding domain, CD28 spacer and transmembrane domain, and CD3 zeta endodomain. Rosenthal does not explicitly teach combining the claimed components in one chimeric receptor or provide sequences for these components such that a chimeric receptor of SEQ ID NO: 32 is taught. Maher teaches a chimeric receptor that comprises each of the component of the claimed chimeric receptor except the TREM2 ligand binding domains. Maher teaches SEQ ID NO: 62 as a chimeric receptor that comprises CD8 alpha signal peptide, CD28 spacer and transmembrane domain, and CD3 zeta endodomain. NP_001258750.1 teaches the sequence for the TREM2 extracellular domain. (2) Rosenthal provides teachings regarding the chimeric receptor components and shows the modularity of these components by providing 21 combinations of these combination. Similarly, Maher also teaches chimeric receptors with modular components. Thus, an ordinary artisan would combine the teachings of Rosenthal with the sequences taught by Maher and NP_001258750.1 to result in a chimeric receptor with a sequence of SEQ ID NO: 32 wherein each component would perform the expected function. (3). The combination of the various chimeric receptor component would predictably yield a receptor that is a chimera combining components from distinct molecules as claimed resulting in SEQ ID NO:32.
Therefore, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR. Therefore, it would be obvious to a person of ordinary skill in the art to combine the teachings of Rosenthal with the sequences taught by Maher and NP_001258750.1 to yield a predictable result of a chimeric receptor with a sequence of SEQ ID NO: 32
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Allowable Subject Matter
Elected species for chimeric receptor i.e. SEQ ID NO. 44 in claim 16(iv) is not known in the prior art. It comprises a deletion of residues 154-156 upstream of a known sheddase cut site (H157). However, this specific deletion and its associated function was not known in the art.
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632