DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-7, 9, and 11-20) and the below-listed species in the reply filed on 12/15/2025 is acknowledged.
Elected Species:
CDR1, CDR2, and CDR3 regions corresponding to SEQ ID NOs: 199, 200, and 201;
Monomeric variable domains corresponding to SEQ ID NOs: 50, 205, and 206, each of which comprise all of the above-listed CDR1, CDR2, and CDR3 regions; and
A bispecific molecule (as pertains to claim 15).
Claim Status
Claims 8 and 10 have been cancelled as requested in the amendment filed on 12/15/2025. Following the amendment, claims 1-7, 9, and 11-22 are pending in the instant application.
Claims 21-22 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 12/15/2025, there being no allowable generic or linking claim.
Claims 1-7, 9, and 11-20 are under examination in the instant office action.
Priority
Receipt is acknowledged of certified copies of papers corresponding to PCT/CN2021/072534 required by 37 CFR 1.55. It is further noted that the certified copy is in English, and as such foreign priority to PCT/CN2021/072534 has been perfected.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 09/30/2020. It is noted, however, that applicant has not filed a certified copy of the PCT/CN2020/119648 application as required by 37 CFR 1.55.
Claims 1-7, 9, and 11-20 have an effective filing date of January 18, 2021 corresponding to PCT/CN2021/072534.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/12/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because Figures 3-6 and 12 comprise text that is blurry and difficult to read. 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.
Specification
The use of the terms, for example, FACS, Nanobodies, PRIMESCRIPT, TRIZOL, iFluor, GraphPad Prism, and FlexStation, which are trade names or marks used in commerce, have been noted in this application. 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 terms.
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.
Claim Objections
Claims 2-3 are objected to because of the following informalities: the claim. Appropriate correction is required.
Claim 12 is 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.
Claim Interpretation
With regard to sequence language utilized in the instant claims, the following is noted:
Under broadest reasonable interpretation (BRI), the recitation of “comprising the amino acid sequences of…” is being interpreted as closed sequence language wherein the full-length sequences that are recited are required (see, for example, claim 1);
Under BRI, the recitation of “comprises an amino acid sequence having at least 80%, 85%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence selected from the group consisting of…” is being interpreted as closed sequence language wherein a sequence satisfying the above limitation must have at least 80% identity to the recited full-length sequences (see, for example, claim 7);
Under BRI, the recitation of “comprising an amino acid sequence selected from the group consisting of SEQ ID NOs…” is being interpreted as open sequence language wherein a sequence satisfying the above limitation need only comprise two consecutive amino acids comprised within a full-length sequence from the listed group (see, for example, claim 11);
Under BRI, the recitation of “comprising the amino acid sequence selected from the group consisting of SEQ ID NOs…” is being interpreted as closed sequence language wherein a sequence satisfying the above limitation must comprise a full-length sequence from the listed group (see, for example, claim 12).
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 1-2, 4-7, 9, 11, and 13-20 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to an isolated antibody, or an antigen-binding portion thereof, comprising a monomeric variable domain comprising a CDR1, CDR2, and CDR3 region comprising the amino acid sequences of SEQ ID NOs: 199, 200, and 201, respectively, or a variant thereof comprising up to about 3 amino acid substitutions in any one or more of CDR1, CDR2, and CDR3. Thus, the claims encompass a vast genus of antibodies, or antigen binding fragments thereof, comprising the amino acid sequences of SEQ ID NOs: 199, 200, and 201, respectively, or a variants thereof.
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The instant specification discloses 50 distinct and/or highly homologous single domain antibody clones, described by their full-length CDR1, CDR2, and CDR3 region sequences, on Pages 41-43 (see the table reproduced below).
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It is specifically noted that the instant specification only contemplates antibodies, and fragments thereof, that have the function of binding to the Claudin 18.2 (CLDN18.2) antigen.
Thus, the instant specification discloses making 50 structurally distinct single domain antibodies that function to bind CLDN18.2, wherein said single domain antibodies are described by their complete CDR1, CDR2, and CDR3 sequences. The specification fails to disclose any other CDR1, CDR2, and CDR3 sequence variants having upwards of 3 amino acid substitutions in each of CDR1, CDR2, and CDR3.
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative antibody variants, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In this case, the only factor present in the claims is a recitation of the partial sequence structure (i.e., recited CDR1, CDR2, and CDDR3 sequences and variants thereof) as stated above. It is noted that as presently claimed, the genus of antibodies comprises thousands of possible antibody variants. The instant specification fails to describe structural features common to the members of the antibody genus, and which features constitute a substantial portion of the genus because the instant specification fails to disclose representative antibody variants. The instant specification fails to describe a representative number of antibody sequence variants for the genus of antibodies claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed antibodies.
The claims broadly encompass any sequence variant having upwards of three amino acid substitutions in each of CDR1, CDR2, and CDR3 SEQ ID NOs: 199, 200, and 201, respectively. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of an antibody comprising SEQ ID NOs: 199, 200, and 201 to the structure of any variants. Therefore, one could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the claimed variant antibodies, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies, or fragments thereof, comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 199, 200, and 201, or variants thereof, that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending claim 1 to recite: An isolated antibody, or an antigen-binding portion thereof, that binds Claudin 18.2 comprising:
a monomeric variable domain comprising a CDR1 region, a CDR2 region, and a CDR3 region comprising the amino acid sequences of:
(1) SEQ ID NOs: 199, 200, and 201, respectively;
(2) SEQ ID NOs: 55, 56, and 57, respectively;
(3) SEQ ID NOs: 58, 59, and 60, respectively;
(4) SEQ ID NOs: 61, 62, and 63, respectively;
(5) SEQ ID NOs: 64, 65, and 66, respectively;
(6) SEQ ID NOs: 76, 77, and 78, respectively;
(7) SEQ ID NOs: 82, 83, and 84, respectively;
(8) SEQ ID NOs: 85, 86, and 87, respectively;
(9) SEQ ID NOs: 88, 89, and 90, respectively;
(10) SEQ ID NOs: 91, 92, and 93, respectively;
(11) SEQ ID NOs: 94, 95, and 96, respectively;
(12) SEQ ID NOs: 103, 104, and 105, respectively;
(13) SEQ ID NOs: 106, 107, and 108, respectively;
(14) SEQ ID NOs: 112, 113, and 114, respectively;
(15) SEQ ID NOs: 115, 116, and 117, respectively;
(16) SEQ ID NOs: 121, 122, and 123, respectively;
(17) SEQ ID NOs: 124, 125, and 126, respectively;
(18) SEQ ID NOs: 127, 128, and 129, respectively;
(19) SEQ ID NOs: 133, 134, and 135, respectively;
(20) SEQ ID NOs: 136, 137, and 138, respectively;
(21) SEQ ID NOs: 139, 140, and 141, respectively;
(22) SEQ ID NOs: 142, 143, and 144, respectively;
(23) SEQ ID NOs: 145, 146, and 147, respectively;
(24) SEQ ID NOs: 148, 149, and 150, respectively;
(25) SEQ ID NOs: 151, 152, and 153, respectively;
(26) SEQ ID NOs: 154, 155, and 156, respectively;
(27) SEQ ID NOs: 157, 158, and 159, respectively;
(28) SEQ ID NOs: 160, 161, and 162, respectively;
(29) SEQ ID NOs: 163, 164, and 165, respectively;
(30) SEQ ID NOs: 169, 170, and 171, respectively;
(31) SEQ ID NOs: 172, 173, and 174, respectively;
(32) SEQ ID NOs: 175, 176, and 177, respectively;
(33) SEQ ID NOs: 178, 179, and 180, respectively;
(34) SEQ ID NOs: 181, 182, and 183, respectively;
(35) SEQ ID NOs: 184, 185, and 186, respectively;
(36) SEQ ID NOs: 190, 191, and 192, respectively;
(37) SEQ ID NOs: 193, 194, and 195, respectively;
(38) SEQ ID NOs: 196, 197, and 198, respectively;
(39) SEQ ID NOs: 52, 53, and 54, respectively.
Subsequently dependent claims and/or other independent claims should be similarly amended to remove possible CDR1, CDR2, and CDR3 variants and to recite the antigen to which the antibodies or antigen-binding fragments thereof bind.
Claim 6 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for camelid, chimeric, or humanized antibodies or antigen-binding fragments thereof, does not reasonably provide enablement for fully human antibodies or antigen-binding fragments thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims. This is a SCOPE OF ENABLEMENT rejection.
The Breadth of the Claims
Claim 6 is drawn to an isolated antibody, or an antigen-binding portion thereof, comprising a monomeric variable domain comprising a CDR1, CDR2, and CDR3 region comprising the amino acid sequences of SEQ ID NOs: 199, 200, and 201, respectively, or a variant thereof comprising up to about 3 amino acid substitutions in any one or more of CDR1, CDR2, and CDR3, wherein the antibody or antigen-binding fragment thereof is a camelid, chimeric, human, or humanized. However, based on the instant disclosure (see for example, instant specification Example 1 at Pages 22-23), it appears that the disclosed single domain antibody CDR sequences of instant claim 1 are not human CDRs, but rather are derived from llamas, and therefore the antibodies of the instant disclosure cannot be fully human antibodies. As such, the full scope of claim 6 as pertains to human antibodies is not enabled.
The State of the Prior Art/Level of Predictability in the Art
As disclosed by Bernett et. al. (J. Mol. Biol., 2010, 396, 1474-1490; herein after referred to as “Bernett”), deriving fully human antibodies from transgenic mice or full human antibody libraries was well known and understood in the prior art, and Bernett further disclosed a novel method of generating fully human mAbs from nonhuman variable regions using information from the human germline repertoire comprising the rational engineering of residues within and proximal to CDRs and the VH/VL interface by iteratively exploring substitutions to the closest human germline sequences using semi-automated computational methods to generate fully human antibodies comprising over 40 substitutions relative to the parental murine variable regions with a large number of substitutions occurring in the CDRs (Abstract; Figure 2; see entire document). Thus, Bernett establishes known methods of producing fully human antibodies, including transgenic animals and fully human antibody libraries, or generating fully human antibodies from murine sequences; however the production of fully human antibodies from non-human sequences requires extensive sequence modifications (e.g., over 40 substitutions total) wherein many substitutions occur within the CDRs themselves. Thus, while fully human antibodies may be generated from non-human parental antibodies, significant modification and more specifically CDR modification is required.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
Example 1 of the instant specification discloses the generation of anti-Claudin 18.2 single domain antibodies, wherein llamas were immunized with recombinant human Claudin18.2-His proteins, and after multiple rounds of immunization a blood sample was taken and peripheral blood lymphocytes were isolated; total RNA was extracted from the isolated lymphocytes as a starting material fo RT-PCR and amplification of single domain antibody encoding gene fragments from which VHH PCR fragments were purified and inserted into plasmids to generate a phage display library which was then panned (see Pages 22-23). Taken together, the instant specification demonstrates that the only working examples for producing antibodies of the invention yields non-human antibodies. No working examples of the production of fully-human antibodies are provided.
In view of the state of the prior art, lack of the predictability of the art to which the invention pertains as evidenced by Bernett above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make functional, fully human antibodies or antigen-binding fragments thereof comprising a monomeric variable domain comprising a CDR1, CDR2, and CDR3 region comprising the amino acid sequences of SEQ ID NOs: 199, 200, and 201, respectively, or a variant thereof comprising up to about 3 amino acid substitutions in any one or more of CDR1, CDR2, and CDR3, with a reasonable expectation of success.
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 1-2, 4-7, 9, and 13-20 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.
The term “about” in claims 1 and 2 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Absent a specific definition of the term “about”, it is unclear as to what is the maximum number of amino acid substitutions that may be made to CDR1, CDR2, and/or CDR3; thus the claims are considered to be indefinite. Claims 4-7, 9, and 13-20 are included in this rejection as they depend from and/or incorporate claim 1.
Further regarding claim 4, the phrase "preferably" 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). As currently presented, it is unclear if the recitation of “human Claudin 18.2” is intended to be exemplary, or if the recitation is intended to be limiting.
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.
Claim 11 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2012/0183549 A1 (herein after referred to as "Bradley").
With regard to claim 11, it is specifically noted that as presented the claim is drawn to any antibody or antigen-binding fragment thereof comprising a monomeric variable domain that comprises an amino acid sequence selected from instantly elected SEQ ID NOs: 50, 205, and 206. As detailed above, the recitation of “comprising an amino acid sequence selected from the group consisting of SEQ ID NOs…” is being interpreted as open sequence language wherein a sequence satisfying the above limitation need only comprise two consecutive amino acids comprised within a full-length sequence from the listed group.
Bradley discloses polypeptides directed against or specifically binding to chemokine receptor CXCR2 and in particular to polypeptides capable of modulating signal transduction from CXCR2 (Abstract). In one embodiment, Bradley teaches a biparatopic nanobody (i.e., single domain antibody, comprising a monomeric variable domain) comprises the amino acid sequence set forth in SEQ ID NO: 215 or a sequence of amino acids having at least 80%, at least 85%, at least 90% or at least 95% amino acid sequence identity with SEQ ID NO: 21 (Paragraph 0176). The sequence alignments of Bradley SEQ ID NO: 215 (denoted as “Db”) and instant SEQ ID NOs: 50, 205, and 206, respectively (denoted as “Qy”) are reproduced below.
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Thus, Bradley discloses an antibody or antigen-binding fragment thereof that comprises a monomeric variable domain which comprises at least two consecutive amino acids comprised within instant SEQ ID NOs: 50, 205, and 206. As such, Bradley anticipates instant claim 11.
Art-Free Subject Matter
It is noted that the instantly elected antibody species comprising CDR1, CDR2, and CDR3 regions corresponding to full-length SEQ ID NOs: 199, 200, and 201 and monomeric variable domains corresponding to full-length SEQ ID NOs: 50, 205, and 206 (each of which comprise all of the above-listed CDR1, CDR2, and CDR3 regions) have been thoroughly searched and are free of the prior art.
As noted above, claim 12 is 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
Claims 1-7, 9, and 11-22 are pending. Claims 21-22 are withdrawn. Claims 3 and 12 are objected to. Claims 1-2, 4-7, 9, 11, and 13-20 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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 at (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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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642