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 .
DETAILED ACTION
Claims 34-35 and 55-71 are pending.
Claims 36, 37, and 53 are canceled.
Claims 34-35 and 55-71 are currently amended.
Claims 34-35 and 55-71 are under examination on the merits.
Rejections Withdrawn
35 U.S.C. 112(b)
The rejection of claims 58, 60, and 61-66 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a joint inventor (or for applications subject to pre- AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of the claim amendments, dated 06/17/2026.
Rejections Maintained
35 U.S.C. 112(a)
The rejection of claims 34-37 and 53-71 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 is maintained.
Response to Arguments
In Applicant Arguments, dated 06/17/2026, Applicant asserts that “[t]he claims presented herein are directed to a method of inhibiting a PD-1/PD-L1-mediated biological activity using an antibody that binds PD-1 and PD-L1 and blocks their interaction. The claimed invention therefore resides in the functional application of antibodies exhibiting defined binding and blocking activities in a known biological pathway, rather than in the de novo identification of novel antibody structures. This distinction is critical under Federal Circuit case law.” Applicant further asserts that “[t]he Office acknowledges that Applicant discloses numerous anti-PD-1 and anti-PD-L1 heavy chain variable regions and a common light chain, as reflected, for example, in claims 61-66 and 67. (Office Action, pp. 4-5, 9-12). The specification therefore does not merely define the claimed antibodies functionally but instead provides substantial structural disclosure of multiple antigen-binding regions within the relevant antibody class. Moreover, the PD-1/PD-L1 signaling pathway and its therapeutic modulation via blocking antibodies were well established at the time of filing, as reflected by the Examiner's reliance on benchmark antibodies…”
Applicant further asserts that possession of the claimed invention is demonstrated in multiple ways: “First, the specification discloses numerous structurally distinct anti-PD-1 and anti-PD-L1 antigen-binding domains, including specific VH sequences and combinations thereof, thereby providing concrete examples within the claimed class. (Office Action, pp. 4-5, 9-10). Second, the claims require defined functional characteristics, namely binding to PD-1 and PD-L1 and blocking their interaction, which correspond to a well-understood biological mechanism that was widely known and predictable within this antibody class. (Office Action, p. 5). Third, the specification and claims operate in the context of established immune checkpoint biology, where it was known that antibodies binding PD-1 and/or PD-L1 can modulate T-cell activation. The Office's reliance on known therapeutic antibodies as benchmarks underscores that the claimed activity is not based on an unknown or unpredictable mechanism. (Office Action, pp. 8-9). Taken together, this demonstrates that Applicant was in possession of the claimed invention.”
Applicant’s arguments have been fully considered but are not deemed persuasive. It is initially noted that numerous anti-PD-1 and anti-PD-L1 blocking antibodies have been adequately described; however given the structural variability within the claimed genus and the high level of unpredictability in the antibody arts, said numerous anti-PD-1 and anti-PD-L1 blocking antibodies that have been adequately described are not sufficient to describe the genus as a whole.
The claims are drawn to an antibody that comprises a first variable domain that can bind to PD-1 and a second variable domain that can bind to PD-L1, wherein the binding of the first variable domain to PD-1 blocks the binding of PD-1 to PD-L1 and/or the binding of the second variable domain that can bind to PD-L1 blocks the binding of PD-1 to PD-L1. Absent empirical determination, one skilled in the art would be unable to readily envision which anti-PD-1/anti-PD-L1 antibodies meet the limitations of the claims. For example Fenwick et al. (J Clin Oncol 34, 3072, 2016) teach that “[m]onoclonal antibodies (mAbs) that act through PD-1 blockade have had significant clinical success as cancer immunotherapeutic agents particularly in melanoma and non-small cell lung cancers with considerably lower toxicities compared to similar therapies. Current anti-PD-1 Abs have relied on the blockade of the PD-1/PD-L1 interaction… Our studies show that antagonistic mAbs targeting PD-1 can be blocking or non-blocking of the PD-1/PD-L1 interaction…” Based upon these teachings, one skilled in the art would appreciate that anti-PD-1/anti-PD-L1 antibodies may be blocking or non-blocking antibodies, and non-blocking anti-PD-1/anti-PD-L1 antibodies would not be expected to meet the limitations of the claims.
The findings of Fenwick et al. are not surprising, because the ability of an antibody to bind a particular antigen, alone, does not characterize what other properties the antibody may or may not possess. It is well-recognized in the art that antibodies will display markedly different and unpredictable properties depending on the epitope in an antigen to which a particular antibody specifically binds. Stancovski et al. (PNAS, 88: 8691-8695, 1991) developed a panel of monoclonal antibodies specific to HER-2, an art-known tumor antigen, and Stancovski et al. discovered that although each antibody bound the HER-2 antigen, said antibodies displayed a range of different properties, see Abstract and p. 8694, Table 1. Two of the anti-HER-2 antibodies almost completely inhibited tumor growth, two anti-HER-2 antibodies displayed moderate inhibitory effects, and yet another anti-HER-2 antibody accelerated tumor growth, p. 8694, Table 1. Additionally, said panel of anti-HER-2 antibodies demonstrated a range of apparent affinities and a range of abilities to induce complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and tyrosine phosphorylation, p. 8694, Table 1, and p. 8692, second column, second full paragraph. Furthermore, similar to Stancovski et al., Jiang et al. (J. Biol. Chem., 280: 4656-4662, 2005) teach that while many anti-HER-2 antibodies inhibit the proliferation of cancer cells, other anti-HER-2 antibodies actively stimulate cancer growth, see p. 4656, second column, final paragraph. Importantly, Jiang et al. add that “[i]t is well known that different biological effects are associated with the epitope specificity of the antibodies.” See p. 4656, second column, final paragraph. Based upon the teachings of Stancovski et al. and Jiang et al., one skilled in the art would reason that antibodies specific for the same target protein may have different effects depending upon the epitope specificity of a particular target protein-specific antibody. Accordingly in view of these teachings and absent evidence to the contrary, one skilled in the art would appreciate that the functional characteristics of antibodies binding to the same antigen will differ significantly depending upon epitope specificity, and as such in the absence of screening methodologies, one skilled in the art would be unable to determine whether a particular anti-PD-1 or anti-PD-L1 antibody is a blocking or non-blocking antibody.
Furthermore line 6 of claim 34 recites “providing a system comprising said first and second cell with an antibody or a variant of said antibody comprising a first variable domain that can bind to an extracellular part of PD-1, a second variable domain that can bind to an extracellular part of PD-L1, and a constant domain…” Claims 61-66 recite numerous anti-PD-1 and anti-PD-L1 heavy chain variable regions (VHs), which are adequately described by amino acid sequence; however variants of said antibodies have not been adequately described. As stated in the Non-Final Rejection, dated 03/19/2026, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR residues comprised within the recited VHs could be changed such that the resultant variant CDR residues form an antigen-binding site capable of binding PD-1 (or PD-L1). The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general, guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of heavy chain CDR amino acid sequences, that correlate with the ability to bind PD-1 (or PD-L1), it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met for claims 61-66.
The rejection of the claims under 35 U.S.C. 112(a), written description, have been deemed proper and are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 extension fee 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 NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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