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 .
The preliminary amendment filed 4-3-2023 has been entered into the record. Claims 1-20, 23, 30, 36 and 38 are pending. Claims 2-18 and 20 are withdrawn from consideration.
Election/Restrictions
Applicant's election without traverse of :
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but argued as encompassed by variable regions set fort as SEQ ID NO:297 and 298 in the reply filed on 7-24-2025 is acknowledged. The traversal is on the ground(s) that claim 1 is generic to all the species, including the elected species. This is found persuasive. The species however are not linked by a technical feature that defines over the art as set forth in the Written Opinion of the International Searching Authority, the remainder of the species are withdrawn from consideration. Claims 1, 19, 23, 30, 36 and 38 are under examination. Claim 19 is not in sequence compliance, see compliance issue set forth below. Claim 20 is withdrawn from consideration as it is not drawn to a method of making the elected monoclonal antibody and fragment thereof. Claims 2-18 are withdrawn as drawn to non-elected species.
The requirement is still deemed proper and is therefore made FINAL.
Sequence Compliance
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located at claim 19 are not represented by a specific sequence identifier. The specific referenced sequence identifiers in claim 19 iii), v) and vi) recite specific claimed variables at specific positions. In contrast the CDRs provided in SEQ ID NO: 278, 303 and 281 indicates that any amino acid can be at those positions. As such, the recited sequences are not followed by a unique sequence identifier specific to the claimed subsequences of the generic sequences of claim 1.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Information Disclosure Statement
The information disclosure statements filed 9-12-2024, 10-12-2024 and 7-24-2025 have been considered. An initialed copy is enclosed.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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.
At paragraph [621] page 159 the hyperlink https://doi.org/10.1016/j.cobme.2019.06.003 need to be so modified.
Claim Rejections - 35 USC § 112
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 1, 23 and 30 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.
The claims are drawn to monoclonal antibodies or antigen binding fragments thereof having the properties of: (1) selective inhibition of TGFbeta1 activation, (2) binds to each of human LTBP1-proTGFbeta1 and/or human LTBP3-proTGFbeta1, (3) monovalent dissociation rate of 10.0e-4 (1/s) and (4) a KD of< 1.0 nM. The specification at Table 3, page 33-34, teach limited embodiments of combinations of specific CDRs having very particular substitutions with limited combinations with other CDR changes (see Table 3, pages 33-34). The art teaches that changes to the CDRs lead to unpredictable effects on binding properties of antibodies . Rudikoff et al (PNAS, 1982) demonstrates that a single amino acid substitution alters antigen-binding specificity. Furthermore, Brown et al (Journal of immunology 1996) that VH CDR2 has a tolerance to a single but not multiple amino acid replacements. The effect of the vast majority of substitutions alone or in combination on the claimed properties of the antibodies have not been taught by the specification for the claimed genus of antibodies. The claims encompass an enormous number of individual position changes and then additionally provide complexity by the combination of individual changes. These two factors provide for enumerable variations within the genus. Other than the disclosed position variations, the specification does not teach the effect on the binding properties of the monoclonal antibody or antigen binding fragments thereof. The limited variation disclosed does not support the enormous variation claimed because the specification does not provide for a structure-function correlation for a representative number of species within the genus. One skilled in the art would be unable to envision the effect of a randomly selected amino acid on the binding properties set forth in the claim.
The structures of the polypeptides comprising antigen-binding domains which bind and have the functional properties as claimed are not adequately described. In AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., Ill USPQ2d 1780 (Fed. Cir. 2014) AbbVie had claims to functionally claimed antibodies and Centocor presented evidence that the antibodies described in AbbVie's patents were not representative of other members of the functionally claimed genus. The decision states, “When a patent claims a genus using functional language to define a desired result, ‘the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.’ Id. at 1349. We have held that '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.’ Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). Here, the claimed invention is a class of fully human antibodies that are defined by their high affinity and neutralizing activity to human IL-12, a known antigen. AbbVie's expert conceded that the '128 and '485 patents do not disclose structural features common to the members of the claimed genus.” In the instant application, while a limited number of antibodies that binds has been produced, only specific mutations at specific positions are disclosed. These mutations are disclosed in combination with other specific CDRs. These antibodies have not been described in a way to support a generic claim to any/all antibodies with any variation at positions alone or in combination that bind to an antigen and have the functional properties as claimed. The disclosure of a few species rarely is sufficient to provide support for a genus especially considering a lack of disclosure of structure or disclosure of a correlation between structure and function for the scope of the variation for which patent protection is sought.
The AbbVie decision considers how large of a genus is involved and what species of the genus are described in the patent. With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that “merely recite a description of the problem to be solved while claiming all solutions to it and ... cover any compound later actually invented and determined to fall within the claim's functional boundaries.”).
In the instant application, the specification and claims draw a fence around a perceived genus, but the genus is not adequately described. The claims encompass variations in 8 different amino acids in different heavy and light chain CDR positions with any of 20 amino acids, in any combination such that functionality is preserved. While the art supports variation being permitted in the framework regions if the CDR amino acid sequence structure is preserved, the claims are not so limited. No reasonable structure-function correlation has been established that is commensurate in scope with the disclosure and the claims. The specification does not describe representative examples to support the full scope of the claims.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, states 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, for purposes of the written description inquiry, is whatever is now claimed (see page 1117).
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(1), the court states, “An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.”
Thus, given the level of skill and knowledge and predictability in the art, those of skill in the art would not conclude that the applicant was in possession of the claimed genera of monoclonal antibodies and antigen-binding fragments which bind based on disclosures set forth above. "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004). For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly.
Further, it is not sufficient to define the genus solely by its principal biological property, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. Per the Enzo court's example, (Enzo Biochem, Inc. v. Gen-Probe Inc., 63 USPQ2d 1609 (CA FC 2002) at 1616) of a description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) couched "in terms of its function of lessening inflammation of tissues" which, the court stated, "fails to distinguish any steroid from others having the same activity or function" and the expression "an antibiotic penicillin" fails to distinguish a particular penicillin molecule from others possessing the same activity and which therefore, fails to satisfy the written description requirement. Similarly, the function of a protein to bind and have specific functional characteristics does not distinguish a particular protein from any other protein and as such, fails to satisfy the written-description requirement. Applicant has not disclosed any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Applicant has provided limited variation that falls vastly short of substitution of 20 amino acids at a single position, let alone 8 positions in combination. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. (Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406). 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 at page 1116). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
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, 19, 23, 30, 36 and 38 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 inventor, or for pre-AIA the applicant regards as the invention.
Claim 1 and dependent claims 19, 23, 30, 36 and 38 are confusing in that the independent states that the antibody or fragment binds “each of” LTBP1 and/or LTBP3 with specific properties. If it binds “each of” how then can it bind one “or” the other with the specifically claimed properties. Given the language it is unclear what the antibody actually binds and what properties are specifically present. If the Applicant wishes to include the alternative binding, then removal of “each of” should resolve the issue as the term “and/or” encompasses both alternatives.
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)(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, 19, 23 and 30 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Datta et al (WO 2020/014473 A1, filed July 11, 2019 with priority to 2018; of record).
Datta et al teach monoclonal antibody Ab2 having SEQ ID NO:13 and 15 and comprise the following CDRs that meet the limitation set for in the claims. SEQ ID NOS:13 and 15 comprise an embodiment of the claimed heavy and variable chain CDRs:
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The disclosed monoclonal antibody Ab2 and its disclosed CDRs meet the limitations of claims 1 and 19 (see Table 4, pages 26-27). Datta et al teach the use of Ab2 and others for the treatment of Fibrotic conditions at paragraphs 259-270 using the antibodies. Datta et al also teach pharmaceutical compositions comprising the antibodies and antigen binding fragments thereof (see paragraphs 412-425). Inasmuch as the structure of the antibody meets the limitation of the claims, the functional properties (binding, dissociation rate and KD) are necessarily present. For the foregoing reasons the claims are anticipated.
Claims 1, 19, 23 and 30 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Datta et al (US Patent 11,130,803 or US Patent 12,122,823 or US20250215072A1 all with priority to July 11, 2019 with provisional priority to 2018 all having identical disclosures).
Datta et al teach monoclonal antibody Ab2 having SEQ ID NO:246 and 241 and comprise the following CDRs that meet the limitation set for in the claims. SEQ ID NOS:246 and 241 comprise an embodiment of the claimed heavy and variable chain CDRs:
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The disclosed monoclonal antibody Ab2 and its disclosed CDRs meet the limitations of claims 1 and 19 (see Table 5, columns 61-62; Table 7, columns 67-68). Datta et al teach the use of Ab2 and others for the treatment of Fibrotic conditions at columns 195-200 using the antibodies. Datta et al also teach pharmaceutical compositions comprising the antibodies and antigen binding fragments thereof (see column 78, line 22- column 79, line 20). Inasmuch as the structure of the antibody meets the limitation of the claims, the functional properties (binding, dissociation rate and KD) are necessarily present. For the foregoing reasons the claims are anticipated.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Patricia Duffy whose telephone number is (571)272-0855. The examiner can normally be reached 8:00 am - 4 pm.
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/Patricia Duffy/ Primary Examiner, Art Unit 1645