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 .
Claim Status
Claims 7 and 12 are cancelled. Claims 1-6, 8-11, and 13-22 as filed on 18 January 2024 are pending and are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must 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.
Specification
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.
Applicant is directed to page 5 of the specification in [0026].
Please review the entire specification to confirm no other hypertext links are present.
Information Disclosure Statement
The information disclosure statement filed 23 October 2023 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because the three Foreign references were not attached. It has been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
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, 3-4, 6, 9-11, 13-14, and 16-22 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.
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).
Scope of the Claimed Genus
Claims 1 and 19 are to a single-domain antibody that binds PD-1 and comprises a variable heavy chain comprising 3 CDRs with mixing and matching of the sequences of the CDRs.
Claims 3-4, 6, 9-11, 13-14, 16-18, and 20-22 do not provide any limitations to the CDRs of the single domain antibodies of the claims.
Summary of Species Disclosed in the original specification
Applicant discloses 6 single domain antibodies with 3 defined sets of CDRs in Table 1b and shown below.
VHH
CDR1
CDR2
CDR3
1A4
SEQ ID NO:
5
9
17
1A9
SEQ ID NO:
5
10
18
1H1
SEQ ID NO:
6
11
19
1D3
SEQ ID NO:
6
10
18
2C4
SEQ ID NO:
6
12
20
2D9
SEQ ID NO:
6
9
21
State of the Relevant Art
Programmed cell death-1 (PD-1) is a type I transmembrane protein of 268 amino acids comprising extracellular immunoglobulin variable region (IgV) like domains, hydrophobic transmembrane region, and an intracellular region Wu (WO 2018050039 A1) (PTO-892) (page 1 last 3 lines). Binding PD-1 with a single domain antibodies with defined CDRs was known in the art (Abstract and Figure 5). Binding of PD-1 by traditional or single domain antibodies to block PD-L1 binding is used for immunotherapy of tumors (page 2 in par 2).
The binding to a target by a nanobody comes from its CDR sequences. While
conventional antibodies comprise two heavy and two light chains with 6 CDRs nanobodies comprise a single heavy chain of 3 CDRs (Bannas et. al. (Front. Immunol. 8:1-13. (2017)) (PTO-892) (Figures 1-2). CDR3 loop of the nanobody or VHH provides most of the diversity and specificity of the nanobody (Figure 2). The CDR3 of a nanobody varies in length from 3 to -28 amino acids increasing the potential interaction surface with target antigens. This compensate for the lack of VL in the nanobody creating distinct orientation of nanobodies when they bind their targets when compared to conventional antibodies (Page 2 in col 2 in last paragraph, page 3 in col 1 in lines 1- 9).
Variation in the CDR sequences change the stability of VHH when humanizing a VHH so a consensus framework region of a VHH with variation to the CDRs, as allowed by the claims, would have varying activity as an antibody (Rouet et. al. Journal of Biological Chemistry. 290(198):11905-11917 (2015) (PTO-892) (page 11915 in col 1 in par 2-4).
It was accepted in the art that all three CDRs were required for VHH binding and the sequences of those CDRs determine binding activity and specificity.
Are the disclosed species representative of the claimed genus?
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.
The specification discloses six single domain antibodies comprising three fully defined CDRs.
As shown in the art changes to sequences of the CDRs would result in changes to the binding activity in unpredictable ways.
Given the variability encompassed by the a genus of single domain antibodies which comprises three CDRs that provide its binding activity, describing six single domain antibody species cannot be considered representative of the genus.
Identifying characteristics and structure/function correlation
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. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
As noted above the binding activity of a single domain antibody is from the structure of the three CDRs and comes from the sequence of those CDRs in a specific combination. The disclosure of one set of CDRs does not provide one of skill in the art with the binding activity of different combinations of CDRs or changes to the sequences of the CDRs. Changes to CDR combinations and sequences change the binding activity of single domain antibodies in unpredictable ways.
Conclusion:
For the reasons presented above, one of skill in the art would not consider the disclosed 6 species as representative of the genus of PD-1 binding single domain antibodies where mixing and matching of CDRs or variation in the amino acid sequence of the CDRs is encompassed in the claims. The CDRs are the structure that provides function to single-domain antibodies and the disclosed 6 species only provides structure/function correlation for the 6 disclosed species and not the additional antibodies of the claims.
Therefore, the skilled artisan would not reasonably conclude that the inventors had full possession of single domain antibodies that bind PD-1 as broadly claimed at the time the application was filed. 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, Applicant was not in possession of the invention as claimed.
Allowable Subject Matter
Claims 2, 5, 8, and 15 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA EDGINGTON-GIORDANO whose telephone number is (571)272-8232. The examiner can normally be reached Mon - Fri 8:00 - 5:00.
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, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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