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 .
Claims 3-153 have been cancelled. Claims 154-166 have been newly added.
Election/Restrictions
Applicant’s election of an anti-LAP antibody having the CDRs recited in new claim 154 in the reply filed on 3/4/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-2 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected antibodies as indicated by the 3/4/2026 claim set, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/4/2026.
Specification
The disclosure is objected to because of the following informalities:
A replacement sequence listing was filed 3/4/2026. This sequence listing adds SEQ ID NOS: 2654-2719. These sequence identifiers are now referenced with respect to Figures 6-10, using the language “in order of appearance.” This is confusing as these figures do not show particular sequences in any discernible order. At least for example, which sequence identifiers correspond to the HCDR2 sequences (third from left) in Figure 6. The sequence identifiers are not clearly associated with the sequences in the figures. Note that SEQ ID NOS: 2654-2658 are each five amino acid sequence with four wild-card positions. It appears that most of the new sequence identifiers include wild-card positions. Applicant’s response should provide a detailed and clear explanation of sequence correspondence, particularly to demonstrate that no new matter has been introduced.
As set forth in the restriction requirement mailed 9/4/2025, parts of the sequences in these figures remain illegible. Applicant’s 3/4/2026 did not address this.
Appropriate correction is required.
Claim Objections
Claim 154 is objected to because of the following informalities: The independent claim should indicate the meaning of the “LAP” acronym. See latency associated peptide referring to the amino terminal domain of the human TGF31 precursor peptide as defined on page 70, lines 21-23 of the specification. Appropriate correction is required.
Claim 160 is objected to because of the following informalities: Claim 160 recites “SEQ ID NOs: 2619” (plural) where a single sequence identifier is being referenced. Appropriate correction is required.
Claim 166 is objected to because of the following informalities: Claim 166 ends in two periods (“..”). Appropriate correction is required.
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 154-158 and 161-166 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.
Claim 154 is directed in part to an anti-LAP antibody where only the VH CDRs responsible for antigen binding are defined or where only the VL CDRs responsible for antigen binding are defined. The claim does not require both the VH and VL. See recitation of “and/or” in the claim. Likewise, dependent claims 155-158 and 161-166 do not require both the VH and VL recited in claim 154. Only claims 159-160 require both the VH and VL.
The specification does not adequately describe anti-LAP antibodies where the VH having the CDRs recited in claim 154 are paired with a VL of unknown or variant structure.
The specification does not adequately describe anti-LAP antibodies where the VL having the CDRs recited in claim 154 are paired with a VH of unknown or variant structure.
Kranz et al. (Proc. Natl Acad. Sci, USA, 78(9):5807-5811, 1981) showed that in mixing heavy and light chains from six monoclonal anti-fluorescyl antibodies, heterologous heavy and light chain mixtures did not form anti-fluorescyl active sites (p. 5809, col. 1, first part of second paragraph). In another experiment (supra, p. 5809, col. 1, third paragraph), “Of the 30 possible heterologous H and L chain combinations, 13 did not reassociate within detectable limits..., 13 reassociated but with less affinity than the homologous association,.. and 4 associated with greater affinity than the homologous reassociation....” In the instant claims, the VH of claim 154 can be paired with any VL or the VL of claim 154 can be paired with any VH. Herold et al. (Scientific Reports, 7:12276, DOI:10.1038/s41598-01 7-12519-9, Sept. 2017, p. 2, end of second paragraph), looked at VH/VL interfaces and how changes affected antigen binding and found, “Our results on the effects of mutations on domain structure, stability, association and antigen binding together with CDR exchange experiments reveal complex relationships between structural and functional properties within the VL and VH domains.” It was discussed that (p. 11, start of 3rd paragraph), “The relationship between structure, stability and binding affinity of VH and VL is still unclear. This is an important aspect for understanding antibody architecture both as the basis of our immune system and also in the context of the engineering of antibodies for therapeutic purposes. In this context, it was found that in mutants an increase in affinity is often accompanied by a decrease in stability and vice versa - and these consequences are difficult to predict.” The reference concludes (p. 14, end of 2nd paragraph and 3rd paragraph), “[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way…Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding.” Herold et al. and Kranz et al. illustrate the unpredictability of pairing either the VH with a VL of unknown structure or the VL with a VH of unknown structure with respect to binding properties.
The specification does not adequately describe the genus of antibodies embraced by the claims.
Claims 161-166 are 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 methods of treatment by administering antibody 06BLM as discussed below, does not reasonably provide enablement for all methods embraced by the claims. 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 and use the invention commensurate in scope with these claims.
The VH and VL CDRs recited in claim 154 correspond to antibody 06BLM (Kabat numbering scheme). See at least Table 45A at page 317 of the specification. It is an affinity-matured 20E6 IgG variant. See at least page 315 of the specification. The binding affinity of antibody 06BLM is disclosed in Table 46 at page 339 of the specification.
Claim 161 is directed to a method of treating cancer by administering a therapeutically effective amount of the antibody or antigen binding fragment of claim 154. Claim 154 does not require any particular therapeutic effect.
Page 89, lines 22-28, of the specification defines the term “treatment” to include prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder or recurring disease or disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
Page 92, lines 9-15, of the specification further defines the term “treatment” to include reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease.
Example 17 on page 340 of the specification shows binding of the LAP/TGβ1 antibody 06BLM to tumor infiltrating immune cells.
Examples 18-24 don’t test the claimed antibody 06BLM (also referenced as 54BLH or 42BMD; see Table 45D at page 339).
At least for example, one of ordinary skill in the art at the time of the effective filing date would have understood that administering anti-LAP antibodies could inhibit TGFβ1 activation on immunosuppressive cells in subjects having cancers such as those in instant claim 164. See at least claims of Fox et al. (U.S. Patent No. 11,230,601).
However, this does not demonstrate enablement of the breadth of therapeutic effects encompassed by the claims. One of ordinary skill at the time of the effective filing date would not have understood that administering the claimed antibody would prevent or cure any cancer, including all of those listed in claims 162-164. The additional therapies recited in claims 165-166 are not required to have any particular therapeutic effect.
With respect to reversing all symptoms associated with cancer, at least for example many cancers cause tissue destruction. At least for example, there is no evidence of record nor reason to believe that administration of the claimed antibody would reverse or repair damage to bone in bone cancer. At least for example, there is no evidence of record nor reason to believe that administration of the claimed antibody would reverse or repair damage to skin in skin cancer. At least for example, there is no evidence of record nor reason to believe that administration of the claimed antibody would reverse brain tissue damage (including any resulting cognitive or motor deficits) in glioblastoma.
The specification does not enable the scope of the claims.
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 161-163 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.
Claim 161 is confusing in reciting “of any of claim 154.” Claim 154 is directed to one antibody.
The term “characterized by abnormal TGFβ activity” in claim 162 is a relative term which renders the claim indefinite. The term “abnormal” 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. While page 70 of the specification discusses the intent of “abnormal” activity, the term is not disclosed in such a way as to meaningfully apprise one of ordinary skill in the art as to the specific TGFβ levels encompassed by the claims.
The term “associated with infiltration” in claim 163 is a relative term which renders the claim indefinite. The term “associated” 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.
Claims 159-160 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.
The VH and VL CDRs recited in claim 154 correspond to antibody 06BLM (Kabat numbering scheme). See at least Table 45A at page 317 of the specification.
SEQ ID NOS: 2589 and 2604 in claim 159 correspond to the VH and VL, respectively, for antibody 06BLM. See at least Table 45B at page 329 of the specification. SEQ ID NO: 2589 contains the VH CDRs recited in claim 154 and SEQ ID NO: 2604 contains the VL CDRs recited in claim 154.
SEQ ID NOS: 2619 and 2634 in claim 160 correspond to the heavy and light chain, respectively, for antibody 06BLM. See at least Table 45C at page 332 of the specification.
SEQ ID NO: 2619 contains SEQ ID NO: 2589 and SEQ ID NO: 2634 contains SEQ ID NO: 2604.
The prior art of record does not disclose anti-LAP antibodies having SEQ ID NOS: 2589 and 2604 (claim 159); SEQ ID NOS: 2619 and 2634 (claim 160); or the CDRs of SEQ ID NOS: 2229-2234. Note that the variation permitted by claim 159 must occur outside of the CDRs or the claim would not be properly dependent upon claim 154 which requires the CDR sequences.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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