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 .
DETAILED ACTION
Claim Status
Applicant’s amendment filed October 10, 2023 was received and entered.
Claims 6, 18, and 21 have been amended.
Claims 3, 5, 17, 19, 22-31, and 35-41 have been canceled.
Claims 1-2, 4, 6-16, 18, 20-21, and 32-34 are pending and under consideration.
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. This application is a 371 of PCT/CN2021/120909 filed September 27, 2021, which claims priority to foreign application PCTCN2020118184 filed September 27, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
However, 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).
The disclosure of the foreign priority document, PCTCN2020118184 filed September 27, 2020, 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 one or more claims of this application.
The instant claims are drawn to a chimeric antigen receptor (CAR) comprising an antigen-binding domain specific for the extra domain B (EDB) of fibronectin and an extracellular domain and/or a transmembrane (TM) domain of a membrane protein selected from CD3z, CD3e, CD3g, CD3d, CD4, CD8, CD28, OX40 or CD137.
The specification of prior application PCTCN2020118184 does not contemplate an extracellular domain and/or a transmembrane (TM) domain of a membrane protein from CD3z, CD3e, CD3g, or CD3d as recited in claims 1 and 32. The first disclosure of an extracellular domain and/or a transmembrane (TM) domain of a membrane protein from CD3z, CD3e, CD3g, or CD3d is PCT/CN2021/120909 filed September 27, 2021. Accordingly, claims 1-2, 4, 6-16, 18, 20-21, and 32-34 of the instant application are not entitled to the benefit of the prior application date of September 27, 2020.
Should Applicant disagree with the examiner’s factual determination as to the disclosure of the claim limitations, Applicant may point out the particular places within application PCTCN2020118184 which discloses the specific subject matter.
Accordingly, PCT/CN2021/120909 with the filing date of September 27, 2021 will be used for the purpose of applying art.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on March 28, 2023 and October 10, 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because the use of the terms Nanobody™, BiTE®, DART®, Anticalin™, Adnectin™, DARPin™, and Avimer™, which are trade names or marks used in commerce, has been noted in this application. The terms 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.
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.
Appropriate correction is required.
The disclosure is objected to because the incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
The attempt to incorporate subject matter into this application by reference to CA A06864.2 is ineffective because it is deemed “essential" as the scFv antigen-binding portion of the CAR recited in the instant claims is based on CA A06864.2 [pg. 11]. The “essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. See 37 C.F.R. 1.57 (d).
The incorporation by reference will not be effective until correction is made to comply with 37 CFR 1.57(c), (d), or (e). If the incorporated material is relied upon to meet any outstanding objection, rejection, or other requirement imposed by the Office, the correction must be made within any time period set by the Office for responding to the objection, rejection, or other requirement for the incorporation to be effective. Compliance will not be held in abeyance with respect to responding to the objection, rejection, or other requirement for the incorporation to be effective. In no case may the correction be made later than the close of prosecution as defined in 37 CFR 1.114(b), or abandonment of the application, whichever occurs earlier.
Any correction inserting material by amendment that was previously incorporated by reference must be accompanied by a statement that the material being inserted is the material incorporated by reference and the amendment contains no new matter. 37 CFR 1.57(g).
Claim Objections
Claims 1-2, 4, 6, 10-11, 21, and 32 are objected to for the following informalities:
Claims 1 and 32 - “Immunoreceptor Tyrosine-based Activation Motif” should not be capitalized.
Claim 2 (line 2) - should read “a derivative of a VHH”.
Claim 2 (line 3) - should read “a derivative of a VH or VL”.
Claim 2 (line 4) - ‘lipocalins” should not be pluralized.
Claim 2 (line 5) - should read “(10th FN3 domain of fibronectin ):”.
Claims 4 and 6 - should read “hinge/spacer” not “hinge / spacer”.
Claim 10 - should read “OX40”.
Claim 11 (lines 2-3) - should read “a CD8a extracellular domain, a CD8a transmembrane domain, a 4-1BB intracellular domain, and a CD3z intracellular domain”.
Claim 21 - should read “selected from the group consisting of a T cell, an NK cell and a macrophage.
Appropriate correction is required.
Claim Interpretation
As set forth in below, claim 14 is rejected under 35 U.S.C. 112(b) as being indefinite for reciting the phrase “such as”. For the purpose of compact prosecution, the claim is being interpreted as requiring any polynucleotide encoding the instantly claimed CAR, and is not limited to the polynucleotide of SEQ ID NO: 2.
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.
Claims 1-2, 4, 6-16, 18, 20-21, and 33 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claims 1-2 recite the phrase "e.g.", which render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 4, 6-16, 18, 20-21, and 33 are included in the rejection because they depend from or otherwise require all the limitations of a rejected claim and fail to clarify the issue.
Claim 2 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claim 2 contains the trademark/trade names nanobody, BiTE, DART, anticalin, adnectin, DARPin, and avimer.
Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a camelid VHH, a bispecific T cell engager, a dual affinity retargeting bispecific antibody, a lipocalin derivative, the 10th FN3 domain of fibronectin, a designed ankyrin repeat protein, and an avidity multimer, accordingly, the identification/description is indefinite.
Appropriate correction is required.
Claim 2 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claim 2 recites types of antigen-binding domains, including examples and/or acronyms in parenthesis. However, it is unclear if the claim is limited to the examples/acronyms in the parenthesis, or if the claim includes additional unrecited examples. For example, line 3 recites “a bispecific T cell engager (BiTE, a bispecific antibody)”. It is unclear if the claim is limited to a BiTE, or if any bispecific antibody is within the scope of the claim.
Claim 7 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claim 7 recites the limitation “wherein (3) comprises the costimulatory domain”. There is no antecedent basis for “the costimulatory domain” in claim 1.
Claims 11-13 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claim 11 recites the limitation "the CAR of claim 1, comprising as the scFv…". The CAR of claim 1 does not recite an scFv, therefore, there is insufficient antecedent basis for this limitation in the claim.
Claims 12-13 are included in the rejection because they depend from or otherwise require all the limitations of the rejected claim and fail to clarify the issue.
Claims 11-13 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claim 11 recites "the scFv of residues 21-236 of SEQ ID NO: 1”, however, it is what the scFv is. The instant specification discloses that the scFv is based on CA A06864.2, however, this reference was not found during search and examination.
Claims 12-13 are included in the rejection because they depend from or otherwise require all the limitations of the rejected claim and fail to clarify the issue.
Claims 12-16 and 18 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claims 12 and 14 recite the phrase the phrase "such as", which render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 13, 15-16, and 18 are included in the rejection because they depend from or otherwise require all the limitations of the rejected claim and fail to clarify the issue.
Claim 13 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claim 13 recites the limitation "a polypeptide of SEQ ID NO: 1". There is insufficient antecedent basis for this limitation in the claim.
Claim 13 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claim 13 recites the limitation "a polypeptide of SEQ ID NO: 1", however, the phrase “a polypeptide” implies that you can have more than one polypeptide, which does not make sense in relation to SEQ ID NO: 1. Therefore, one of ordinary skill in the art cannot ascertain the metes and bounds of the claim.
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.
Claims 1-2, 4, 6-16, 18, 20-21, and 32-34 are rejected under 35 U.S.C. 112(a), 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, at the time the application was filed, had possession of the claimed invention.
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, reduction to drawings, 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 MPEP § 2163.
Claims 1 and 32 are drawn to a chimeric antigen receptor (CAR) comprising an antigen-binding domain specific for the extra domain B (EDB) of fibronectin.
The claims encompass a large genus of antigen-binding domains that can be incorporated into a CAR, comprised of different combinations of amino acid sequences, which represent structurally distinct polypeptides. The state of the art is such that there are many types of antigen-binding domains that can be incorporated to a CAR construct, including the diverse group of antigen binding domains recited in instant claim 2.
Sterner (2021) teaches that historically, the antigen-binding domains are derived from the variable heavy (VH) and light (VL) chains of monoclonal antibodies, connected with a flexible linker to form a single-chain variable fragment (scFv). Several characteristics of the scFv impact CAR function beyond simply recognizing and binding the target epitope. For instance, the mode of interaction among the VH and VL chains as well as the complementarity-determining regions’ relative positions impact the affinity and specificity of the CAR for its target epitope. Affinity is a particularly important antigen-binding domain parameter as it fundamentally determines CAR function. In order to recognize antigens on tumor cells, induce CAR signaling, and activate T cells, the CARs antigen binding affinity must be sufficiently high but not high enough to result in activation induced death of the CAR expressing T cell and trigger toxicities. However, even scFvs with similar affinities can differentially impact CAR-T cell function [pg. 3-4]. In the case of scFvs, variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain sequences. As taught by Janeway et al. (2001), the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. See also Rabia et al. (2018; pg. 4), which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antigen binding specificity. The diversity is further magnified when considering bispecific antibody fragments. However, the claims do not provide the amino acid sequences for any CDR regions of the antigen-binding domain.
Claim 11 further limits the CAR antigen-binding domain as an scFv comprising residues 21-236 of SEQ ID NO: 1, however, the amino acid sequences of the 6 CDRs are not disclosed.
More recently, Hanssens et al. (2021) teaches alternative antigen binding domains have been incorporated into CAR constructs, such as shark or camelid VHH comprising 3 VH CDR regions, and other single domain antibodies (sdAbs). Although sdAb-CARs counter the aggregation problem associated with scFv‐based CARs, this design does not fence off concerns about potential immunogenicity and unpredictability in behavior due to the nonhuman origin of these molecules. Other CAR designs incorporate protein scaffolds with a designed specificity. For example, DARPins are a class of genetically engineered antibody‐mimetic proteins and are comprised of two or three repeat units of 33 amino acids each. Repeat proteins are common in nature and they are smaller in size, less prone to aggregation, more thermodynamically stable, and considered less immunogenic compared to murine scFvs. Another class of scaffold protein‐based CAR‐T cells ensures tumor targeting via the incorporation of antigen‐specific adnectins. These are proteins derived from the 10th Type III domain of human fibronectin (10Fn3), which is a small and stable protein scaffold that contains three mutable loops, responsible for target binding [Section 3]. However, the claims do not recite the amino acid residues of any protein scaffold that bind EDB of fibronectin.
As such, the claims encompass a broad genus of structurally different antigen-binding domains, derived from both human and nonhuman species, with different amino acid sequences and different affinities or pharmacokinetic properties.
The specification discloses the structure (i.e., amino acid sequence) of 15 CAR constructs comprising the scFV based on CA A06864.2 fused with different combinations of extracellular, transmembrane, and/or intracellular signaling domains [pg. 18-20], and 1 bispecific CAR construct comprising the scFV based on CA A06864.2 fused with the scFv of an anti-CD3e antibody [pg. 21]. However, the CDR regions for the scFvs are not disclosed. Therefore, the instant application has not provided a sufficient description showing possession of the necessary 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 genus of antigen-binding domains encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002). In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "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. The invention is, for purposes of the 'written description’ inquiry, whatever is now claimed." (See Vas-Cath, p. 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath, p. 1116).
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Given the claimed broad class of antigen-binding domains that bind the EDB of fibronectin, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making antibodies with the “limitations above” and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claims 2, 4, 6-16, 18, 20-21, and 34 are included in the rejection because they depend from or otherwise require all the limitations of a rejected independent claim.
Claim 2 is rejected under 35 U.S.C. 112(a), 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, at the time the application was filed, had possession of the claimed invention.
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, reduction to drawings, 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 MPEP § 2163.
Claim 2 is drawn to a selection of antigen-binding domains, including a derivative of VHH, a derivative of a VH or VL domain, or a derivative of lipocalin.
The claim encompasses a large genus of VHH derivatives, VH or VL derivatives, and lipocalin derivatives, comprised of different combinations of amino acid sequences representing structurally distinct polypeptides. The state of the art on VHH production is extremely complex. As taught by Harmsen and Haard (2007), VHH obtained from camelid species can be engineered to generate multivalent or bispecific formats, or to modulate serum half-life using [see Conclusion]. Similar genetic engineering techniques can be applied to domain antibodies and lipocalins to generate derivatives of the parent antigen-binding domain.
The instant claim recites a camelid Ig is a derivative of a VHH, a dAb is a derivative of a VH or VL domain, and an anticalin is a derivative of a lipocalin. However, apart from the recited examples, the instant specification does not provide any definition for a “derivative” of a VHH, a VH, a VL, or a lipocalin. Therefore, the instant application has not provided a sufficient description showing possession of the necessary 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 genus of antigen-binding domains encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002). In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "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. The invention is, for purposes of the 'written description’ inquiry, whatever is now claimed." (See Vas-Cath, p. 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath, p. 1116).
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Given the claimed broad class of VHH, VH, VL, and lipocalin derivatives, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making antibodies with the “limitations above” and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4, 6-10, 14, 16, 18, and 20-21 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Crea et al. (WO 2018/232372) (“Crea”). This reference qualifies as prior art under both 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2).
The instant claims are drawn to a chimeric antigen receptor (CAR) comprising an antigen-binding domain specific for the extra domain B (EDB) of fibronectin, an extracellular domain and/or a transmembrane (TM) domain of a membrane protein selected from CD3z, CD3e, CD3g, CD3d, CD4, CD8, CD28, OX40 or CD137, and an intracellular ITAM domain of CD3z, with one or more costimulatory domains selected from CD28, CD27, 4-1BB, or OX40. Further comprising a hinge/spacer of CD8a between the antigen-binding domain and the TM. The CAR is expressed on the surface of a T cell and is capable of activating the T cell upon binding soluble EDB, a membrane-bound EDB, and/or EDB in extracellular matrices. The antigen-binding domain can be an scFv or bispecific. Also claimed is a polynucleotide encoding the CAR, a lentiviral vector comprising the polynucleotide, and a T cell, NK cell, or macrophage expressing the polynucleotide; a method of inhibiting angiogenesis in a subject with a solid tumor or inflammatory condition by administering a therapeutically effective amount of an immune cell expressing the CAR.
Crea discloses a chimeric antigen receptor (CAR) for binding with a target antigen, comprising i) at least one antigen specific targeting region comprising a fibronectin type 3 (FN3) domain polypeptide; ii) a transmembrane domain; and iii) an intracellular signaling domain [claim 1], wherein the transmembrane domain is selected from transmembrane domains of a type I transmembrane protein, an alpha, beta or zeta chain of a T cell receptor, CD28, CD3 epsilon, CD4, CD8, CD134 (OX40), and CD137 [claim 18], wherein the intracellular signaling domain is an immunoreceptor tyrosine-based activation motif (ITAM) bearing cytoplasmic receptor [claim 21], wherein the CAR further comprises at least one costimulatory domain [claim 19] (instant claim 1); selected from the group of costimulatory domains of CD28, CD137 (4-IBB), CD134 (OX40), and CD27 [claim 20] (instant claims 7-10). The CAR further comprises an extracellular spacer domain comprised of a CD8 hinge [claims 8-9] (instant claims 4, 6). Crea discloses that the FN3 domain polypeptide comprises the 10th fibronectin type 3 module of human fibronectin [claim 7] (instant claim 2).
Crea further discloses a nucleic acid sequence encoding the CAR [claim 57], a lentiviral expression vector comprising the nucleic acid sequence [claims 58, 61], an engineered cell comprising the nucleic acid sequence or expression vector, wherein the cell is a T cell, natural killer (NK) cell, or a macrophage [claims 63-64, 66] (instant claims 14, 16, 18, 20-21).
Regarding T cell activation upon binding EDB as recited in instant claim 1, Crea discloses the identical structure as recited in the instant claims. As such, the CAR disclosed by Crea would inherently perform the same function as recited in the instant claims.
MPEP § 2112 provides guidance as to the Examiner's burden of proof for a rejection of claims under 35 U.S.C. 102 or 103 based upon the express, implicit, and inherent disclosures of a prior art reference. The case law clearly states that something which is old does not become patentable upon the discovery of a new property. “[T]he 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.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999).
Thus, the claiming of a new use, new function or unknown property that is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). Further, the court has held that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) (“[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.”); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999).
The case law specifically applies to the instant application where Applicant has claimed a composition in terms of a function, property or characteristic of immune stimulation and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference. The examiner's assertion of inherency is based upon the structural similarity between the composition of the prior art and the claimed composition.
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established and the burden of proof rests upon the Applicant to demonstrate that the prior art does not necessarily or inherently possess the characteristics of Applicant' s claimed product. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977)). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Therefore, absent a showing of any difference, the product disclosed by the prior art is deemed to anticipate the claimed product.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Crea et al. (WO 2018/232372) (“Crea”).
The instant claims are drawn to a method of inhibiting angiogenesis in a subject with a solid tumor or inflammatory condition by administering a therapeutically effective amount of an immune cell expressing a CAR comprising an antigen-binding domain specific for the extra domain B (EDB) of fibronectin, (2) a transmembrane (TM) domain of a membrane protein selected from CD3z, CD38e, CD3d, CD4, CD8, CD28, OX40 or CD137; and, (3) an intracellular ITAM of CD3z, with or without a costimulatory domain.
Crea discloses the identical CAR structure recited in the instant claims as set forth in the rejection above. In addition, Crea teaches a method of treating cancer in a subject in need comprising introducing the engineered cell expressing the CAR [claim 70], wherein the cancer is a solid tumor [claim 76]. Preferably the target antigen is specific for cancer, such as fibronectin extra domain B. The FN3 CAR can also target antigens specific for inflammatory diseases [00142-144]. Specifically, a therapeutically effective amount of the genetically modified cells expressing the FN3 CAR protein may be formulated for administration [00211, 00217]. The FN3 CAR-T cell binds an antigen present on a target cell (e.g., solid tumor cell), mediating cytotoxicity and killing, or inhibiting growth of the target cell. Target cells include solid tumor cells [00216] (instant claims 32-34).
The teachings of Crea differ from the instant claimed invention in that even though the identical CAR structure targeting fibronectin extra domain B for the treatment of solid tumors is disclosed, the CAR-T cells are not explicitly taught for the use in mediating cancer related angiogenesis.
However, Crea does teach that FN3 CAR-T cells can be used to inhibit the growth of target cells. The instant specification does not provide a specific definition for angiogenesis, but discloses that it is a prerequisite for tumor growths and metastasis [Example 3, pg. 38]. Therefore, the methods taught by Crea would encompass angiogenesis as recited in the instant claims. As such, the prior art provided prima facie case of obviousness.
Claims 1 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Crea et al. (WO 2018/232372) (“Crea”) as applied to claims 1-2, 4, 6-10, 14, 16, 18, 20-21, and 32-34 above, further in view of Bondanza et al. (US 2017/0247428) (“Bondanza”).
The instant claims are drawn to a chimeric antigen receptor (CAR) comprising an antigen-binding domain specific for the extra domain B (EDB) of fibronectin, an extracellular domain and/or a transmembrane (TM) domain of a membrane protein selected from CD3z, CD3e, CD3g, CD3d, CD4, CD8, CD28, OX40 or CD137, and an intracellular ITAM domain of CD3z, with one or more costimulatory domains selected from CD28, CD27, 4-1BB, or OX40. Further comprising a hinge/spacer of CD8a between the antigen-binding domain and the TM. The CAR is expressed on the surface of a T cell and is capable of activating the T cell upon binding soluble EDB, a membrane-bound EDB, and/or EDB in extracellular matrices. The antigen-binding domain can be an scFv or bispecific. Also claimed is a polynucleotide encoding the CAR that is codon optimized for expression in a human cell, a lentiviral vector comprising the polynucleotide, and a T cell, NK cell, or macrophage expressing the polynucleotide; a method of inhibiting angiogenesis in a subject with a solid tumor or inflammatory condition by administering a therapeutically effective amount of an immune cell expressing the CAR.
The teachings of Crea are set forth above. Specifically, Crea teaches a nucleic acid encoding an FN3 CAR for production in a mammalian cell [00185-186] for the treatment of a solid tumor in a subject, wherein the subject is a human [0093].
However, Crea does not teach the polynucleotide encoding the CAR is codon optimized for expression in a human cell.
Bondanza teaches methods of engineering CARs wherein all constructs are codon-optimized for expression in humans [0212].
It would have been obvious to one of ordinary skill in the art to engineer the polynucleotide encoding the CAR taught by Crea to be codon-optimized for expression in a human cell because codon-optimized polynucleotides allow the CAR to be expressed in humans, as evidenced by Bondanza. The skilled artisan would recognize that this is a critical step for using the claimed CAR construct to treat human subjects with solid tumors. Accordingly, the combination of prior art references provided a prima facie case of obviousness for the instantly claimed invention.
REQUIREMENT FOR INFORMATION
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the
following information that the examiner has determined is reasonably necessary to the examination of
this application.
Note the standard in 37 C.F.R. 1.57(d):
(d) "Essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. "Essential material" is material that is necessary to:
(1) Provide a written description of the claimed 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 set forth the best mode contemplated by the inventor of carrying out the invention as required by 35 U.S.C. 112(a);
(2) Describe the claimed invention in terms that particularly point out and distinctly claim the invention as required by 35 U.S.C. 112(b); or
(3) Describe the structure, material, or acts that correspond to a claimed means or step for performing a specified function as required by 35 U.S.C. 112(f).
The scFv of the instant invention is based on CA A06864.2 (incorporated by reference) [pg. 21]. As such, CA A06864.2 is deemed to be essential material. However, no matching reference to CA A06864.2 was found during search and examination.
In response to this office action, please submit a copy of CA A06864.2, including an English translation if necessary.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This Office action has an attached requirement for information under 37 CFR 1.105. A complete reply to this Office action must include a complete reply to the attached requirement for information. The time period for reply to the attached requirement coincides with the time period for reply to this Office action.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571) 270-0730. The examiner can normally be reached Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642