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
Newly submitted claims 1 and 8 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: The new antigen binding sites have CDRs of different sequences compared to those in the previous claim set.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. For clarity of the record, the examiner acknowledges that Applicant has canceled this originally elected species and will proceed to the next species chosen by the examiner for examination on the merits.
The examiner selects an antigen binding site with SEQ ID Nos. 170, 171 and 173 as the next species for examination.
Claim Status
Claims 1 and 8 are under examination.
Claims 2-7 and 9-57 are canceled.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/30/2025 is being considered by the examiner.
Objections Withdrawn
Specification
The objection for use of the terms NUVION (0116), CREMOPHOR (0187), and TWEEN (0194), is withdrawn in view of Applicant’s amendments.
Objections Maintained
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 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Here, there are sequences in need of sequence identifiers at 0149.
This rejection stands because no sequence identifiers were added.
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 sequence identifiers, 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.
Claim Objections
Claim 8 remains objected to because there is an extra period after nM in line 2 which must be removed.
Appropriate correction is required.
Rejections Withdrawn
Claim Rejections - 35 USC § 112
The rejection of claims 1 and 8 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of Applicant’s amendments.
The rejection of claims 1 and 8 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 for having new matter is withdrawn in view of Applicant’s amendments.
Rejections Maintained
Claim Rejections - 35 USC § 112
Claims 1 and 8 remain 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 domain antibodies comprising three complete parental CDRs tested and known to bind antigen, does not reasonably provide enablement for similar domain antibody antigen binding sites with truncated/mutated parental CDRs. 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 or use the invention commensurate in scope with these claims.
Examiner’s Response to Traversal: Applicant’s amendments and arguments have been carefully considered but are not found persuasive.
The two new HCDR3s of the claims above are still too short and so for the reasons of record this rejection must stand. Applicant presents no rationale as to why they are complete and thus this rejection is maintained.
Again, all arguments in the prior action are incorporated here as to the entirety of this rejection. For convenience a brief summary of it is below. The examiner notes the protein A binding issue has been addressed and so is not raised again here.
Claim 1, on which claim 8 depends, recites a binding site with only a VH domain comprising CDR1-3 comprising SEQ ID Nos. 170, 171 and 173, respectively. It appears these related CDR combinations are those of CNG-HSA-115 in Table 1. Even if a VH domain comprising these CDRs had been made and tested and shown to bind antigen (HSA), the recited CDR3 is too short to be a Kabat CDR and so is a truncated/mutated version of a CDR3 that would contribute to antigen binding. Again, antibodies comprising mutated CDRs do not have predictable binding function as discussed below.
With respect to functional domain antibodies, Ward (Nature, Vol. 341, Pg. 544-546, 1989, previously cited) teaches that such antibodies, like VHH, have three complete CDRs (Figure 3). However, only 21 supernatants out of 400 tested yielded functional domain antibodies (Pg. 545, Column 1, Paragraph, second). In a second experiment, only 14 binders were found among 2000 colonies (Pg. 545-546, paragraph, spanning). They also note that previously separated heavy and light chains show no evidence for binding by single chains rather than dimers (Pg. 544, Column 2, Paragraph, first). Taken together, it is clear that while domain antibodies can be made against at least some antigens, not just any VH or VL region can bind antigen alone. Claims encompassing use of structures untested are therefore not enabled to their full scope.
Nanobodies/VHHs bind antigen with only three CDRs. Yau (Journal of Immunological Methods, Vol. 297, Pg. 213-224, 2005, previously cited) teaches this on page 214, Column 1, Paragraph, first). All three are important for antigen binding as demonstrated by the randomization of all three CDRs in the work of Yau (Figure 1). Importantly, the work of Yau also demonstrates the unpredictability of nanobody CDR mutation and the ability of identifying a functional nanobody with only one CDR defined. Table 1 shows that CDR mutation leads to unpredictable results, unknown until binding is actually tested. Mutation of CDRs led to loss of substantial antigen binding in several cases, as in Gp3. In addition, one can compare D7 with D8 and see that even when fewer than all three parental CDRs are kept constant, the results are unpredictable. D8 and D7 share a CDR3 but have very different affinities. Thus, all three parental CDRs in a camelid antibody/VHH/nanobody participate and are important for antigen binding. Their mutation leads to unpredictable results. This loss of antigen binding via parental CDR mutation is also known for conventional antibodies. 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. (Proc Natl Acad Sci USA 79: 1979-1983, 1982, previously cited). Rudikoff et al. teach 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.
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given antibody/nanobody modification. Therefore, without data, there is no hope that the mutated CDR set of instant claims will contribute antigen binding function to a VH framework and so the antigen binding site claimed is not enabled.
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Moreover, claims not containing elements critical or essential to the practice of the invention (in this case three parental CDRs), such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
With respect to CDR3 as claimed being truncated, a complete set of CDRs for patent purposes should include CDRs that are known to confer antigen binding to a non-parental framework. As is well known to PHOSITA, Kabat CDRs can be moved to a different framework, such as during humanization, and confer antigen binding. The examiner is unaware of any showing in the art that IMGT CDRs have the same capacity, for example. Therefore, unless a CDR labeling system has been shown to provide CDRs with such capacity, CDRs defined therewith cannot enable an antibody claim. The CDR3 of the instant claims is not a complete CDR as discussed below since it is structurally very different from a Kabat CDR3 and has not been shown to confer antigen binding to a framework.
The art confirms that Chothia CDRs are not complete CDRs. Dubel (Handbook of Therapeutic Antibodies, 2007, Pg. 100-101, previously cited) teaches that Chothia CDRH1 is a structural loop that does not include the complete CDR (Pg. 100, Paragraph, final). They conclude that the analysis of classes by Chothia is based on structural loops rather than the full CDRs (Pg. 100-101, Paragraph, spanning). Thus, Chothia CDR sets cannot be considered complete. They also confirm that Chothia definitions of CDRs change over time and so are not consistently defined (Pg. 101, Paragraph, first). It is further noted that IMGT introduced a range of residues for the same loops and they confusingly term these CDRs (Pg. 101, Paragraph, fourth). Thus, it is clear that the art does not consistently recognize IMGT CDRs as complete.
Johnson and Wu (Methods in Molecular Biology, Antibody Engineering: Methods and Protocols, Vol. 248, Pg. 11-25, 2004, previously cited) teach that complete CDRs of antibodies CDRH1-3 and CDRL1-3 are at least 5, 16, 8, 11, 7, and 9 amino acid residues in length respectively (Pg. 12, Paragraph, second full). In instant claim 1, CDRH3 has 6 residues in SEQ ID NO. 173. This is significantly smaller than the CDR length of Kabat HCDR3 and so would not be expected to confer antigen binding to an antibody framework barring evidence to the contrary. It amounts to no more than a mutated Kabat CDR. Thus, claims 1 and 8 do not only recite a complete set of CDRs known to confer antigen binding to a framework and amount to only a VH having a mutated Kabat CDR. Mutated CDRs would not predictably bind antigen as discussed supra.
Therefore, barring experimental evidence, the claimed antigen binding sites and antibodies comprising the same are not enabled.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibody molecules comprising the three recited CDRs with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
New Objections
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 - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because the "Sequence Listing" part of the disclosure submitted as a PDF file (37 CFR 1.821(c)(2)) or on physical sheets of paper (37 CFR 1.821(c)(3)) is not the same as the CRF of the "Sequence Listing" as required by 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii).
Required response - Applicant must provide:
A replacement "Sequence Listing" as described above in items 1) c) or d) in accordance with 37 CFR 1.825(b)(1)(ii) or (iii); as well as
An amendment specifically directing its entry into the application as required by 37 CFR 1.825(b)(2)(ii);
A statement that identified the locations of any deletions, replacements or additions to the “Sequence Listing” as required by 37 CFR 1.825(b)(3);
A statement that the "Sequence Listing" added by amendment includes no new matter as required by 37 CFR 1.825(b)(5);
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4); and
A statement that the content of the previously-filed CRF is identical to the "Sequence Listing" part of the disclosure added by amendment as required by 37 CFR 1.825(b)(7), where provided under item 1) c) or d) (note that where a "Sequence Listing" part of the disclosure is provided under item 1) a) or b), the text file will also serve as the CRF, and the statement of identity is not required);
OR
A CRF as required by 37 CFR 1.821(e)(1) or 1.821(e)(2); and
A statement that the content of the CRF is identical to the "Sequence Listing" part of the disclosure previously submitted as a PDF file (37 CFR 1.821(c)(2)) or on physical sheets of paper (37 CFR 1.821(c)(3)), as required by 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii).
Specification
The disclosure is objected to because of the following informalities: Pages 43-44 have illegible sequences and cut off sequences. Page 46 is not in English. Table 4 on page 57 lacks digits in the first column and instead has io or i0. Finally, there are multiple typographical errors at 0161 and 0162.
Appropriate correction is required.
New Rejections
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.
Claim 8 is 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 new matter rejection.
Claim 8 requires a binding site comprising all possible CDR combinations of claim 1 (four combinations) to bind HSA with a KD of no lower limit and/or having a melting temperature with no upper limit.
First of all, there is no teaching that any of these four species have even the specified KD of 10nM and/or melting temperature of 60C. The original claim set does not recite the claimed antibody species at all. The original specification also fails to state that the binding site species recited are to have these properties. Rather, it states only that some embodiments, meaning some sites, have them. A genus does not anticipate a species and so the specification at most makes obvious the parameters above for the four sites claimed. Even if one or both parameters were stated for all four combinations above, there is no limit to either KD or temperature going lower or higher respectively and so it is not possible that Applicant has a binding site with just any low or any high value encompassed by the claim.
For all these reasons, the claim limitations are at most obvious from the original disclosure but this is not the same as original contemplation/teaching. Rather, it proves only that such was not taught as it had to be made obvious.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL D ALLEN whose telephone number is (571)270-3497. The examiner can normally be reached Mon-Fri 10-6.
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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/Michael Allen/Primary Examiner, Art Unit 1642