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 with traverse of Group I, claims 1, 3-5, 7-8, 10-11, 13-14, and 20-21, drawn to a monovalent antibody that binds to human galectin-1, pharmaceutical composition containing said antibody and the first named method of use (method of binding hGAL-1) in the reply filed on 6/22/2026 is acknowledged. The traversal is on the ground(s) that the claims of Groups I and II should be examined together as the restriction between these groups is improper under PCT Rule 13.1/13.2.
Applicant’s arguments with respect to the restriction requirement between Groups I and II have been fully considered and are found persuasive, and is hereby withdrawn. Claims 15 and 20, directed to Group II, drawn to a nucleic acid encoding a monovalent antibody and pharmacological composition containing said nucleic acid, are hereby rejoined and fully considered on the merits in this office action.
Claims 1, 3, 5, 7-8, 10-11, 13-15, 20-22, 23, 25, 28, 30, and 32-33 are pending in the instant application.
Claims 23, 25, 28, 30, and 32-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected group, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/22/2026.
Claims 1, 3, 5, 7-8, 10-11, 13-15, and 20-22 are under review for the Applicant elected species.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the reference sequence in Fig. 5 is missing a SEQ ID NO for the “Reference” sequence. 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.
Nucleotide and/or Amino Acid Sequence Disclosures
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:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that the amino acid sequence of the “Reference” sequence for the nanobodies® G1N1 and G1N2 disclosed in the specification (see “Brief Description of the Drawings”, specifically, page 9, lines 10-13) and drawings (see Fig. 5) is missing a SEQ ID NO. Furthermore, the “Reference” sequence is not disclosed in the Sequence Listing XML. Amino acid sequences of 4 or more amino acids require a sequence identifier. Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o 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:
“identity” should read “identify” (page 15, line10);
Appropriate correction is required.
The use of the term nanobody®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. All trademarks referenced herein should be identified as such with the appropriate notation:
Nanobody® (page 9, line 11; page 11, lines 11; etc.)
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 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.
Claim 11 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 11 recites the limitation "monovalent antibody according to claim 1" in line 1 of the claim. The metes and bound of the claim are unclear as there is no antecedent basis for the limitation “monovalent antibody” in claim 1. Thus, there is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(a)
Claims 1, 5, 7-8, 11, 13-15, and 21-22 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. This is a WRITTEN DESCRIPTION rejection.
Scope of the claims
The invention as disclosed in claims 1, 5, 7-8, 11, 13-15, and 20-22 recite a single-domain antibody that specifically binds to hGAL-1 and inhibits its activity. The claims encompass a genus of CDR combinations comprising the heavy chain variable region comprising variability (e.g. at least 80% identity) in the CDRs, which is claimed as having the function of specifically binding to the hGAL-1 antigen. This means that the variability in sequence identity (e.g. at least 80% sequence identity) occurs in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining hGAL-1 binding. Additionally, the instant disclosure does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the CDRs in the heavy chain variable regions such that the obtained structure would still result in performing the requisite functions of the specific binding of hGAL-1 antigen.
Summary of Disclosed Species in the Original Specification
The single-domain antibody that specifically binds to hGAL-1 and inhibits its activity in the Applicant disclosure (e.g. see §Examples 2 and 3 on pages 27-28) represent anti-hGAL-1 single-domain antibodies that the Applicant was in possession of at the time of filing, wherein one of the VHHs (clone D06, referred as G1N1) showed strong binding to GAL-1-specific non-adsorbed phage ELISA while the second clone, G01 (G1N2) showed weak binding (FIG. 4). The amino acid sequences of G1N1 and G1N2 are disclosed in FIG. 5.
However, the specification does not describe the random combination of CDR's fragments to prepare a single-domain antibody that specifically binds to hGAL-1. The specification does not disclose a representative number of single-domain antibodies with the claimed binding characteristics. The disclosed antibodies (e.g. G1N1 and G1N2) have a specific CDR structure that binds a particular hGAL-1. The specification does not, however, disclose a correlation of structure with the function by means of a representative number of hGAL-1 binding domains that have the requisite claimed functional properties. Therefore, the specification does not provide for a structure-function correlation of single-domain antibodies representative of the full scope of the genus. Furthermore, it is clear that the specification does not describe single-domain antibodies with particular functional properties or combinations of different CDRs. The specification does not describe a correlation of the structure of the hGAL-1 binding domain with the functional properties as claimed (e.g. percent identical variants) absent the presence of the specifically disclosed CDRs in specific order that convey the structure that correlates with the binding function as claimed. Variations to the CDRs and to any framework regions that affect binding do not have description for the broad scope of the claims.
State of the Prior Art
At the time of filing, conventional antibody functionality was known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that mutation to CDRs is unpredictable and that each construct requires function testing (Sela-Culang et al, “The structural basis of antibody-antigen recognition”, 2013, Fron. Immuno., 4(302): 1-13; hereinafter Sela-Culang). Sela-Culang reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring conventional antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition (page 1, Abstract; page 3, “The Role of CDRs and their Definition” section). A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized (page 1, “The Motivations for, and Applications of, the Study of Ab-Ag Recognition” Section).
It is well established that changes in the amino acid sequence of the variable region of an antibody create new antibodies with highly unpredictable binding characteristics. See for example Chen et al (Chen et al, “Enhancement and destruction of antibody function by somatic mutation: unequal occurrence is controlled by V gene combinatorial associations”, 1995, The EMBO Journal, 14(12):2784-2794). Chen teaches that the substitution of a single amino acid can totally ablate antigen binding (Figure 1), however, the reference additionally teaches that the same substitution in closely related antibodies can have opposite effects. The authors compared the effects of identical substitution in related antibodies D16 and T15, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. Additionally, Rudikoff et al (Rudikoff et al, “Single amino acid substitution altering antigen-binding specificity”, 1982, PNAS 79:1979-1983) teach that such is necessary and conventional to define an antibody that specifically binds a cognate antigen.
Further, Herold (Herold et al, “Determinants of the assembly and function of antibody variable domains”, 2017, Nature Scientific Reports, 7(12276):1-17; hereinafter Herold) teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected, because antigen binding is affected by each CDR loop differently and changes thereto can, in principle, affect antigen binding affinity in an unpredictable way (page 14, paragraph 2). Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex ( page 14, paragraph 3). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Rudikoff et al, “Single amino acid substitution altering antigen-binding specificity”, 1982, PNAS 79:1979-1983). Rudikoff et al teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Additionally, the prior art has taught single variable domains from species with VH and VL antibody pairing is distinct from other species with single domain only antibodies. (Holliger et al, “Engineered antibody fragments and the rise of single domains” Nature Biotechnology, 2005, 23:1126–1136). Holliger taught despite early excitement concerning the functional activity of single variable heavy domain antibodies, these antibody fragments rarely retained the affinity of the parent antibody and were also poorly soluble and often prone to aggregation (page 1127, left to right column bridging paragraph). Holliger taught while high affinity single variable like domain antibodies are present in camelid, as VhH, and shark, as V-NAR, domains, these single domain antibodies are structurally different, wherein each display long surface loops, often larger than for conventional murine and human antibodies, and are able to penetrate cavities in target antigens, such as enzyme active sites (for example, lysozyme) and canyons in viral and infectious disease biomarkers (page 1127, left to right column bridging paragraph). Holliger taught the structural changes are shown in Fig. 2, wherein superimposition of a human VH domain (Fig. 2b) and a single domain V-NAR(Fig. 2c) has a vastly different CDR3 that does not overlap structurally (Fig. 2d). Holliger taught unlike mouse VH domains, camelid VhH and shark V-NAR domains are in general soluble and can be produced as stable in vitro targeting reagents (page 1127, right column, second paragraph).
At the time of filing, Galectin-1 inhibition had been pursued for three different types of inhibitors: monovalent carbohydrate-based inhibitors, multivalent carbohydrate-based inhibitors, and non-carbohydrate-based inhibitors (page 539, §3.Therapeutic potential of galectin-1 inhibitors; Table 1; Blanchard et al, “Galectin-1 inhibitors and their potential therapeutic applications: a patent review”, March 25, 2016, Expert opinion on therapeutic patents, 26(5):537-554, IDS entered on 11/3/2023; hereinafter Blanchard). Blanchard further discloses that nanobodies (single domain antibodies) were developed to target multiscavenger receptors including galectin-1 in US Patent No. 9,034,325B2, wherein the binding affinities observed for binding to the multiscavenger receptor were in the nanomolar range, although the binding specificity was not addressed (page 545, right column, second paragraph). In fact, Saraiva (US9034325B2, Priority to July 22, 2008; hereinafter Saraiva) discloses several sequences of CDR sequences in Table B-1; however, the disclosure does not identify the binding specificity for the combination of CDR sequences listed in Table B-1 (pages 25, column 44, line 64-page 26, column 46, line 52; Table B-1). Blanchard further discloses that numerous patents have also proposed treating galectin-1 overexpression by antibodies, fragments thereof, and peptides targeting galectin-1 to not only overcome cancer immunosuppression but also circumvent resistance to anti-vasculo-endothelial growth factor treatment, which is an important clinical problem in clinical therapies (page 545, right column, second paragraph).
The prior art, however, does not teach a known structure activity relationship for HCDR1-3 in an anti-hGAL-1 single-domain antibody that would allow prediction of CDR residues that specifically bind to the hGAL-1 antigen. Thus, making changes to the CDR sequence of an antibody sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
For all the foregoing reasons, in view of the substantial genus of variant single-domain antibodies that bind hGAL-1, the numerous factors impinging binding and function of the antibodies to the target and also having the specifically claimed function, and the lack of description of a representative number of single-domain antibodies that function as claimed, the single-domain antibody that specifically binds to hGAL-1 is not described in the specification in such a way as to reasonably convey to one skilled in the art that the Applicant, at the time the application was filed, had possession of the claimed invention. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 3 CDRs in single-domain antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claims 1 and 8 would need to recite the 3 CDRs in the antibody that bind the antigen hGAL-1 without variability in the sequences thereof.
Allowable Subject Matter
Claims 3 and 10 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
Claims 1, 5, 7-8, 11, 13-15, and 20-22 are rejected.
Claims 3 and 10 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jieun Ham whose telephone number is (571)272-7779. The examiner can normally be reached Monday - Friday 7-2.
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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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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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