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 amended claims filed September 3, 2024 are entered. Claims 3, 5-7, 10-15, 17, 20, 22, 24, 26-28, 30, 32-35, 37-38, 40, 42, 44, 46-47, 49-69, and 71-72 have been canceled. Claims 4, 8-9, 16, 18-91, 21, 23, 25, 29, 31, 36, 39, 41, 43, 45, 48, and 70 have been amended.
Claims 1-2, 4, 8-9, 16, 18-19, 21, 23, 25, 29, 31, 36, 39, 41, 43, 45, 48, and 70 are pending and under examination herein.
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. See Figure 10B.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: The Brief Descriptions of Figures 1 and 8 (and the corresponding description in Example 2) recite references to color (blue, red, yellow, and/or green). However, the Drawings are in black and white, and a petition to use color drawings has not been filed for the instant application. References to colors should be omitted in the description of the figure.
Appropriate correction is required.
The disclosure is further objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See pages 56 and 57. 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.
Applicant may obviate this grounds of objection by removing the leading “www.” or “http://” from hyperlinks recited in the specification.
The use of the following terms, which are a trade name or a mark used in commerce, has been noted in this application:
AFFIBODY®
AVIMER®
NANOBODY®
The terms should be accompanied by the generic terminology; furthermore the terms 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.
Drawings
The drawings are objected to because Figures 12-14, 16, 20, and 22 contain references to color (red, green, blue, purple, and/or white). However, the Drawings are in black and white, and a petition to use color drawings has not been filed for the instant application. References to colors should be omitted.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 31, 39, and 70 are objected to because of the following informalities:
Claim 31, item (2) would be clearer if amended to recite “(2) the method further comprises…” based on the wherein clause placed before the listing of alternatives and the construction of the remainder of the claim.
Claim 39 should recite a conjunction (i.e., “and” or “or”) between the step(s) of (i) and (ii) that are recited in the claim.
In claim 70, at line 17, it is suggested that “…CNS, ovarian, melanoma pancreatic cancer, …” should instead recite “… CNS cancer, ovarian cancer, melanoma, pancreatic cancer, …”. In addition, the claim recites at least pancreatic cancer (“pancreatic cancer” in line 17 and “pancreas cancer” in line 19), multiple myeloma (in lines 9 and 18), medulloblastoma (in lines 11 and 13), and retinoblastoma (in lines 11 and 14) in duplicate.
Appropriate correction is 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 2, 9, 16, 43, and 70 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.
Claim 2 recites that the antibody or antigen-binding fragment thereof of claim 1 is an affibody or an avimer. However, the terms “affibody” and “avimer” are understood by those in the art to refer to types of antibody mimetics, which act similarly to antibodies and bind specific antigens, but do not comprise CDRs like conventional monoclonal antibodies and have alternative structures. See, e.g., Zhang (Biotechnology Journal (2024) 19(1): 2300532). An affibody refers to a small antibody mimetic protein with a protein scaffold derived from the B region of Staphylococcal protein A, engineered to bind to a target protein with high affinity. The term “avimer” refers to an artificial protein that is able to specifically bind to certain antigens via multiple binding sites. The claim is indefinite because it is not clear how the “antibody or antigen-binding fragment thereof of claim 1” can be an affibody or avimer when neither of these structures are an antibody.
Further regarding claim 2, the claim contains the following trademarks/trade names (which are used to describe):
AFFIBODY® (a small antibody mimetic protein with a protein scaffold derived from the B region of Staphylococcal protein A, engineered to bind to a target protein with high affinity);
AVIMER® (an artificial protein that is able to specifically bind to certain antigens via multiple binding sites; shorthand for “avidity multimer”); and
NANOBODY® (a single antigen-binding domain of Camelid heavy-chain only antibodies).
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.
Regarding claim 9, the phrase “optionally” in line item (f) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In particular, it is unclear if the specific species set forth in the claim (i.e., “a CAR-T cell, CAR-macrophages, CAR-monocyte”, etc.) are intended to limit of the “CAR-immune cell” recited in line 13. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. The description of examples or preferences is properly set forth in the specification rather than the claims.
Claim 16, which depends from claim 9 and does not remedy this deficiency, is similarly rejected.
Regarding claim 43, the phrase “optionally” in line 3 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In particular, it is unclear if the species of detectable markers (i.e., fluorescent labels, phosphorescent labels, chemiluminescent labels, etc.) are intended to limit the detectable marker recited in line 2. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. The description of examples or preferences is properly set forth in the specification rather than the claims.
Regarding claim 70, the claim is indefinite because the claim in line item (v) recites exemplary language “e.g.” and because said exemplary language is recited in parentheses. The use of parentheses in this manner renders the claim indefinite because it is unclear if the phrases in parentheses are limiting or merely exemplary of the respective tumor types not set forth. Furthermore, as set forth above, examples and preferences in a claim may lead to confusion over the intended scope of the claim. Accordingly, the metes and bounds of the claims cannot be determined and the invention is not set forth with the clarity and particularity necessary to satisfy the requirement set forth in 35 U.S.C. § 112(b) so as permit the skilled artisan to know or determine infringing subject matter.
It is noted for Applicant that limitations which are optional will not be considered as required to meet the limitations of the instant claims for the purposes of applying prior art under 35 U.S.C. §§ 102 and 103.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2 and 41 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
As recited in the 35 U.S.C. § 112(b) rejection above, claim 2 recites that the antibody or antigen-binding fragment thereof of claim 1 is an affibody or an avimer. Because affibodies and avimers are understood in the art to be antibody mimetics, not antibodies or antigen-binding fragments thereof, the claim fails to include all of the limitations of the claim upon which it depends.
Claim 41 recites the method of claim 39, “further comprising the step of administering the cancer treatment”. However, claim 39 recites that “determining the expression of PMEPA-1 on a tumor vascular endothelial cell” in (i) and “determining the expression of PMEPA-1” in (ii) each occur after administering said cancer treatment. Accordingly, the administration step recited in claim 41 does not appear to be further limiting since said administration step seems to have already occurred as set forth in the previous claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 4 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that 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, or it may be satisfied by the 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. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The claimed invention. The nature and scope of the claimed invention at issue in part is the anti-PMEPA-1 antibody recited in claim 4, wherein the antibody comprises an amino acid sequence that has “at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to” an amino acid sequence selected from SEQ ID NOs: 1-7. According to the specification (Table 6; pages 61-62), SEQ ID NOs: 1-7 correspond to exemplary amino acid sequences for nanobody (Nb) clones 1-A4, 1-D5, I-D8, I-H4, II-B1, II-B2, and II-C10, respectively, that bind to PMEPA-1.
In another aspect, the claimed invention is drawn to a composition comprising an agent that induces cell death, wherein said agent is an engineered CAR-T cell comprising a nucleic acid comprising a nucleotide sequence having “at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to” SEQ ID NOs: 42-47, as recited in claim 16. According to the specification (Table 8; pages 61-63), SEQ ID NOs: 42-47 correspond to nucleotide sequences encoding nanobody clones 1-D5, I-D8, I-H4, II-B1, and II-B2, respectively, that bind to PMEPA-1.
These limitations fail to satisfy the written description requirement because the claims define the binding domains by their functional abilities of binding to PMEPA-1 or inducing cell death/inducing an immune response, but the corresponding structures in the claim that are responsible for conferring this function are incompletely defined. Specifically, the structures recited in the claims may comprise 1-10% variability in their respective sequences (which correspond to antigen-binding domains), including within the complementarity determining regions (CDRs) that are responsible for conferring their antigen-binding properties and other functional qualities. This incompletely defined structure is not sufficient for carrying out the instantly claimed functions based on what is understood in the art and in view of the teachings of Applicant's disclosure.
State of the prior art. Schroeder (Journal of Allergy and Clinical Immunology (2010) 125(2, Suppl.2): S41-S52) sets forth that conventional immunoglobulins (antibodies) known in the art are composed of two heavy and two light chains. These chains can be separated functionally into variable domains, which are responsible for antigen binding, and constant domains, which specify effector functions (Abstract). Each variable domain (heavy and light) can be split into three regions of sequence variability (i.e., CDRs). The six heavy and light chain CDRs are paired to form the antigen-binding site as classically defined (e.g., Abstract). It is understood in the art that, for a conventional antibody or immunoglobulin, the structural element that correlates with its function is these six CDRs. As discussed by Sela-Culang (Frontiers in Immunology (2013) 4: 302), “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3, left column, “CDRs Identification”).
While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. Ni (The Protein Journal (2024) 43: 683-696) teaches, “Mutations, even one mutation, introduced in the CDRs through [somatic hypermutation] can change the binding properties and repertoire of antibodies. However, how just one-point mutation can dramatically change the recognition profiles of the antibody is still unclear” (Introduction).
The importance of the CDR sequences in mediating antigen recognition is also true for single domain antibodies. Holt (Trends in Biotechnology (2003) 21(11): 484-490) teaches that domain antibodies (dAbs), which occur naturally in camelid ‘heavy chain’ immunoglobulins and are now produced in fully human form, are the smallest known antigen-binding fragments of antibodies and comprise the robust variable regions of the heavy and light chains (VH and VL) of immunoglobulins. Jovčevska (BioDrugs (2020) 34:11-16) teaches that VHH antibodies share the same structural architecture as the VH domain of human immunoglobulins: four conserved sequence regions (i.e., framework regions) that surround three hypervariable antigen-binding loops (i.e., CDRs). CDR3 is the main contributor for antigen recognition and specificity, whereas CDR1 and CDR2 assist in the binding strength (Section 1.2). Bannas (Frontiers in Immunology (2017) 8: 1603) additionally teaches, “The CDR3 loop of camelid VHHs shows a much broader distribution of lengths (3-28 amino acids) than human VH domains (8-15 amino acids). The long CDR3 of a VHH enlarges the potential interaction surface with the target antigen, thereby compensating in part for the missing VL-domain” (“The Antigen-Binding Modules of Conventional and Heavy Chain Antibodies”, pages 2-3).
Exemplary anti-PMEPA-1 antibodies are disclosed in the art by Karbyshev (Pathol. Oncol. Res. (2017) 24(2): 427-438; cited in IDS), Vo Nguyen (Cancer Science (2014) 105(3): 334-341; cited in IDS), and Saikumar (US 2016/0000735 A1; cited in IDS).
Scope of species disclosed in original specification. Example 2 describes the creation of a yeast display single-domain antibody (sdAb) library to generate and validate sdAbs against the PMEPA-1 ectodomain (page 54). Example 4 further describes the generation of PMEPA-1 nanobody(VHH)-IgG fusion constructs (page 58). Tables 6-7 (pages 61-62) summarize the amino acid sequences of the VHH domains for seven exemplary nanobody clones (1-A4, 1-D5, I-D8, I-H4, II-B1, II-B2, and II-C10; plus three negative controls) and the corresponding three CDRs for six of said clones (1-D5, I-D8, I-H4, II-B1, II-B2, and II-C10). Table 8 (pages 62-64) recites the corresponding nucleotide sequences thereof for said six clones and the three negative controls.
MPEP § 2163 states that 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. In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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.
As outlined above, Applicant expressly describes the structure of six sdAb clones with respect to their VHH amino acid and nucleotide sequences and the corresponding three CDRs which confer their antigen-binding properties. Applicant does not provide a showing of which residue(s) in the binding domain structures (in particular within the CDRs) may be mutated within these exemplary clones, introducing up to 10% variability within the respective VHH sequences, while maintaining the ability of the antibody to bind to PMEPA-1 and/or to induce cell death or an inflammatory response as required by the instant claims.
Conclusion. For the reasons presented above, one of skill in the art would not know which of the countless other anti-PMEPA-1 antibodies encompassed by the highly general structural requirements of the claims would also possess the required functional activity. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of anti-PMEPA-1 antibodies as broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 36 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., an abstract idea and a natural phenomenon) without significantly more. Abstract ideas include mathematical concepts, mental processes (including concepts performed in the human mind), and certain methods of organizing human activity. See MPEP § 2106.04(a). Laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. See MPEP § 2106.04(b).
Claim 36 is directed to a judicial exception without significantly more because the claim is directed to an abstract idea and a natural phenomenon, and this judicial exception is not integrated into a practical application. The claim recites a method of diagnosing or prognosing cancer in a subject comprising the step of “determining the expression of PMEPA-1 on a tumor vascular endothelial cell,” which is drawn to an abstract idea. The claim further recites that “upregulation of expression of PMEPA-1 on the tumor vascular endothelial cell as compared to a control level is indicative of the presence or progression of the cancer”, which is drawn to a natural phenomenon. The natural phenomenon is the correlation between the presence of a specific biomarker, PMEPA-1, and risk or association with presence or progression of a cancer. As evidenced by Sharad (biomolecules (2020) 10: 1221; cited in IDS), overexpression of PMEPA-1 (isoform -a) is detected in multiple solid tumors, including breast cancer, colon cancer, rectal adenocarcinomas, renal cancer, stomach cancer, pancreatic endometrial adenocarcinomas, and prostatic adenocarcinomas (e.g., Section 5). Where a claim is drawn to such a correlation which does not have markedly different characteristics compared to what occurs in nature, the claim is drawn to a natural phenomenon.
A claim that focuses on judicial exception(s) can be shown to recite something "significantly more" than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. While claim 36 further recites an optional further step of “administering a cancer treatment”, this step is not required to be performed under the broadest reasonable interpretation of the claim.
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.
(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.
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.
(1)
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Karbyshev (Pathol. Oncol. Res. (2017) 24(2): 427-438; cited in IDS).
Karbyshev discloses monoclonal antibodies against the C-terminal cytoplasmic region of TMEPAI (also called PMEPA-1) which were generated in rats (e.g., Abstract; Methods).
(2)
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vo Nguyen (Cancer Science (2014) 105(3): 334-341; cited in IDS).
Vo Nguyen discloses monoclonal antibodies against a peptide encoding C-terminal residues 249-287 of human TMEPAI, which were generated in TMEPAI-knockout mice (e.g., Methods; Results).
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.
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.
(1)
Claims 1-2, 8-9, 18-19, 21, 23, 25, 36, 39, 41, 48, and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Saikumar (US 2016/0000735 A1; cited in IDS).
Saikumar describes TMEPAI inhibitory agents, including anti-TMEPAI monoclonal antibodies, having utility in the detection, diagnosis, and treatment of cancer (e.g., ¶ 0036-0085). Saikumar teaches that the antibody molecules of the invention comprise antigen-binding fragments (e.g., F(ab’), F(ab’)2), or that the antibodies may be recombinant antibodies (e.g., recombinant full-length IgG antibodies) or scFvs (e.g., 0049-0075), pertinent to claims 1-2. Regarding claims 18-19, Saikumar teaches pharmaceutical compositions comprising an anti-TMEPAI agent of the invention, which may be formulated comprising a lipid nanoparticle (e.g., ¶ 0007, 0133-0144).
Relevant to claims 8-9, 21, 23, 25, 48, and 70, Saikumar teaches methods of inhibiting a cancer cell that overexpresses TMEPAI or of treating a subject with a TMEPAI-overexpressing cancer (e.g., prostate cancer or lung cancer), which comprises administering an agent (e.g., an intrabody, i.e., an antibody) that inhibits TMEPAI expression or activity (e.g., claims 1-4, 6, 9-14, 16; ¶ 0007-0008). Said methods may comprise co-administering a second anti-cancer agent at the same time as the anti-TMEPAI agent, wherein the second anti-cancer agent is a chemotherapy or immunotherapy (e.g., ¶ 0009, 0156-0170; claims 11-14, 16, 19-24).
Relevant to claims 36, 39, and 41, the methods “may further comprise obtaining information on TMEPAI expression in a cancer cell from said subject” treated in the method, “such as by obtaining a cancer cell or tissue biopsy and assessing TMEPAI mRNA levels” or “assessing TMEPAI protein levels”, either prior to treatment with the anti-TMEPAI agent, after treatment with said agent, or both (e.g., ¶ 0009-0010, 0147-0150; claims 11, 30-35). Saikumar further provides for a method for monitoring a cancer therapy in a patient, comprising (a) obtaining a sample which comprises a cancer cell from a cancer patient undergoing cancer therapy (i.e., an anti-TMEPAI inhibitor agent and/or a TGF-β-based therapy), (b) assessing TMEPAI levels in said cancer cell, and (c) comparing the TMEPAI levels in said cancer cell to pretreatment or earlier assessed TMEPAI levels, wherein a decreased TMEPAI level at the later time point indicates that the patient is benefiting from the therapy (e.g., ¶ 0011).
While Saikumar conceives that the anti-TMEPAI agent of the invention may be selected from one of several formats, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to formulate the compositions of the invention with an inhibitory anti-TMEPAI antibody (e.g., intrabody) and to use such an antibody in the methods described by Saikumar. The skilled artisan would have been motivated to do so because Saikumar teaches that elevated expression of TMEPAI is known to have unfavorable prognostic significance in several cancers (e.g., 0006, 0148), and inhibition of TMEPAI decreases tumor burden and prevents tumor metastasis (e.g., Example 2). There would have been a reasonable expectation of success because antibodies (e.g., intrabodies) are among several art-recognized modalities used by those of skill in the art to target and/or inhibit tumor-associated antigens in methods of detection, diagnosis, and treatment of cancer.
(2)
Claims 1, 29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Saikumar (US 2016/0000735 A1; supra) as applied to claims 1-2, 8-9, 18-19, 21, 23, 25, 36, 39, 41, 48, and 70 above, further in view of Kalina (Clinical Cancer Research (2018) 23(24): 7596-7607).
The teachings of Saikumar are recited in the 35 U.S.C. § 103 rejection above.
However, Saikumar does not expressly teach a cancer treatment method that comprises administering a CAR-T cell comprising an anti-PMEPA-1 antibody or antigen-binding fragment thereof.
Kalina investigated fusion-derived chimeric amino acid sequences (CASQs) that may be a source of tumor neoepitopes in prostate cancer (e.g., Abstract). Kalina observed that 87% of tumors contained gene fusions, 41% of which were found to encode CASQs, one of which included the gene fusion of PMEPA1:ETV4, primarily in intermediate/high-risk patients (e.g., Abstract; Results; Table 2). Kalina suggests that the CASQs could represent compelling targets for chimeric antigen receptor (CAR)-T cell therapy and that clinical trials investigating CAR-T cell therapy for prostate cancer are ongoing (e.g., Discussion).
Based on the further teachings of Kalina, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of treating cancer in which the subject in need thereof is administered a CAR-T cell comprising an anti-PMEPA-1 antibody such as that taught by Saikumar. The skilled artisan would have been motivated to do so because PMEPA-1 is a known tumor-associated antigen associated with poorer prognosis in prostate cancer (as taught by Saikumar), and Kalina teaches that clinical trials investigating CAR-T cell therapy for prostate cancer for other prostate cancer-relevant targets are underway (e.g., Discussion). There would have been a reasonable expectation of success because it was routine and conventional by those skilled in the art at the time of filing of the instantly claimed invention to generate CARs using antibody-based antigen-binding fragments such as those described by Saikumar.
(3)
Claims 1, 43, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Saikumar (US 2016/0000735 A1; supra) as applied to claims 1-2, 8-9, 18-19, 21, 23, 25, 36, 39, 41, 48, and 70 above, further in view of Von Andrian (US 2016/0339113 A1; cited in IDS).
The teachings of Saikumar are recited in the 35 U.S.C. § 103 rejection above.
However, Saikumar does not expressly teach a composition comprising an anti-PMEPA-1 antibody associated with a detectable marker (e.g., a fluorescent label) or use thereof in a medical imaging method.
Von Andrian describes methods for delivering an agent to a microvessel endothelial cell in a subject that comprise administering to the subject a microvessel endothelial cell targeting agent that binds to a protein expressed on the surface of said cell (e.g., Abstract; ¶ 0004). In one aspect of the invention, Von Andrian describes a method of assessing the ability of a venule endothelial cell targeting agent to deliver an agent of the invention to a venule or non-venule endothelial cell, which comprises in situ imaging of the test agent in a venule, tissue, or organ surrounding the venule endothelial cell following administration of said test agent (e.g., ¶ 0150-0157, 0276-0309). Von Andrian teaches embodiments in which the targeting agent comprises a fluorescent reagent (e.g., ¶ 0150-0157).
Based on the further teachings of Von Andrian, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify an anti-PMEPA-1 antibody such as that taught by Saikumar such that the antibody comprises a detectable marker and is administered in a medical imaging method. The skilled artisan would have been motivated to do so because the fluorescent label would facilitate easier detection of the labeled test agent in a tissue of interest. There would have been a reasonable expectation of success because Saikumar teaches that the anti-PMEPA-1 antibodies of the invention are suitable for use in detection and diagnostic methods, and because it was routine and conventional for those skilled in the relevant art to conjugate detectable markers to antibodies and other proteins at the time of filing of the instantly claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
(1)
Claims 1-2, 4, 8-9, 16, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10, 18, 24, 30, 40, 45, 65, 82, 123-124, 131, 149, 155, 161, 186-187, 196, 206, and 209 of co-pending Application No. 19/398,555 (reference application).
Regarding claims 1-2, 4, and 43, the co-pending claims recite a composition comprising a first binder which is an anti-PMEPA-1 antibody having a combination of CDRs identical to those recited in instant claim 4 or a binding domain sequence identical to those set forth in instant SEQ ID NOs: 1-7, wherein the binder is connected to a radioactive isotype via a first linker (co-pending claims 1- 4, 10, 18, 24). Regarding claims 8-9 and 16, co-pending claim 30 recites that the composition comprises a second binder that binds an antigen on the surface of a T cell (i.e., induces an inflammatory response) which is administered with the first binder.
(2)
Claims 1, 18-19, 21, 23, 25, 36, 39, 41, 48, and 70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10, 18, 24, 30, 40, 45, 65, 82, 123-124, 131, 149, 155, 161, 186-187, 196, 206, and 209 of co-pending Application No. 19/398,555 as applied to claims 1-2, 4, 8-9, 16, and 43 above, further in view of Saikumar (US 2016/0000735 A1; supra) and Von Andrian (US 2016/0339113 A1; supra).
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above. In addition, co-pending claim 206 recites a pharmaceutical composition comprising a binder that specifically binds to a protein expressed on an endothelial cell and a pharmaceutically acceptable carrier. Co-pending claim 209 recites a method of selectively delivering a therapeutic composition to a tumor endothelial cell by administering the composition comprising a binder that binds to a protein expressed on an endothelial cell.
The co-pending claims do not expressly recite a pharmaceutical composition comprising an anti-PMEPA-1 antibody (as in claims 18-19), or a method of treating cancer that comprises administering an anti-PMEPA-1 antibody in combination with an agent that induces cell death or induces an inflammatory response (as in claims 21, 23, 25, 48, and 70), or a method of diagnosing/prognosing cancer or determining the efficacy of a cancer treatment (as in claims 36, 39, and 41), or expressly using an antibody labeled with a detectable marker in a medical imaging method (as in claim 45). However, these deficiencies are remedied by Saikumar and Von Andrian as set forth in the 35 U.S.C. § 103 rejections above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to formulate a composition comprising an inhibitory anti-TMEPAI/PMEPA-1 antibody such as that recited in the co-pending claims and to use such an antibody in methods of diagnosis, detection, or treatment of cancer based on the further teachings of Saikumar and Von Andrian. The skilled artisan would have been motivated to do so because Saikumar teaches that elevated expression of TMEPAI is known to have unfavorable prognostic significance in several cancers (e.g., 0006, 0148), and inhibition of TMEPAI decreases tumor burden and prevents tumor metastasis (e.g., Example 2). Furthermore, the skilled artisan would have been motivated to use the radiolabeled binder in a medical imaging method such as that described by Von Andrian because the detectable label would facilitate easier detection of the labeled test agent in a tissue of interest. There would have been a reasonable expectation of success because antibodies are among several art-recognized modalities used to target/inhibit the function of tumor-associated antigens in methods of treatment and to carry out diagnostic or detection-related methods for a biomarker of interest in disease.
(3)
Claims 1, 4, 29, and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10, 18, 24, 30, 40, 45, 65, 82, 123-124, 131, 149, 155, 161, 186-187, 196, 206, and 209 of co-pending Application No. 19/398,555 as applied to claims 1-2, 4, 8-9, 16, and 43 above, further in view of Saikumar (US 2016/0000735 A1; supra) and Kalina (Clinical Cancer Research (2018) 23(24): 7596-7607; supra).
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above. In addition, pertinent to claims 29 and 31, the co-pending claims recite a CAR-immune cell comprising a first binder (a monoclonal antibody, or a nanobody) that specifically binds to PMEPA-1, which comprises the same combination of CDRs or the binding domain sequences as set forth in the instant claims (co-pending claims 123-124, 131, 149, 155). Co-pending claim 209 also recites a method of selectively delivering a therapeutic composition to a tumor endothelial cell by administering the composition comprising a binder that binds to a protein expressed on an endothelial cell.
The co-pending claims do not expressly recite a method of treating cancer that comprises administering the CAR-immune cell, e.g., a CAR-T cell. However, this deficiency is remedied by the teachings of Saikumar and Kalina as set forth in the 35 U.S.C. § 103 rejections above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of treating cancer in which the subject in need thereof is administered a CAR-T cell comprising an anti-PMEPA-1 antibody such as that taught by the co-pending claims. The skilled artisan would have been motivated to do so because Kalina teaches that PMEPA-1 is a known tumor-associated antigen that can be prone to mutational events within a higher risk subgroup of prostate cancer patients and may be targetable by personalized therapy (e.g., Abstract; Discussion). Further, Kalina teaches that clinical trials investigating CAR-T cell therapy for prostate cancer for other prostate cancer-relevant targets are underway (e.g., Discussion). There would have been a reasonable expectation of success because it was routine and conventional by those skilled in the art at the time of filing of the instantly claimed invention to generate CARs using antibody-based antigen-binding fragments such as those described by Saikumar.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
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