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 .
Applicant’s remarks, filed 12/2/2025, are acknowledged and entered into the record. Applicants amended claims 1, 3-4, 7, 9, 11, 14, 17 and 30, and canceled claim 25, in the remarks of 12/2/2025.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2021/019583, filed 2/25/2021; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 62/982476, filed 2/27/2020.
Status of Claims
Claims 1-20, 22, 27-33 and 35-38 are pending and are being examined on the merits.
Claim Objections-Withdrawn
The objections to claims 7, 14 and 17 are withdrawn as applicants amended the claims to correct the informalities.
Claim Objections
Claim 30 is objected to because of the following informalities: Applicants amended claim 30 to recite “antigen-binding fragment thereof claim of 1,”. Applicants have misplaced the identifier (i.e. “of”) such that it does not come before the noun (i.e. “claim 1”). The claim should read as “thereof of claim 1”. Appropriate correction is required.
Claim Interpretation
Claim 10 recites “a VH region having a polypeptide sequence of SEQ ID NO: 1”. The broadest reasonable interpretation of “having a polypeptide sequence of SEQ ID NO: 1” includes any sub-sequence within the recited sequence that constitutes a polypeptide sequence. That is, use of the identifier “a” is open ended and can relate to any sub-sequence found in the listed amino acid sequence. Claim 10 uses the “having a polypeptide sequence of” phrase before each SEQ ID NO listed in subsections (1)-(7). Therefore, any of the sequences listed may comprise any sub-sequence as identified by the phrase “a polypeptide sequence”. If applicants want the claim to require the full amino acid sequences, corresponding to the listed SEQ ID NOs, applicants should amend the claim to be drawn to “having the polypeptide sequence of”. Use of the identifier “the” is closed-ended and specifies a single sequence.
Claim Rejections – Withdrawn
Claim Rejections - 35 USC § 112(b)
The rejection of claims 3-5 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. Specifically, applicants amended the claims to remove the indefinite language; that being the limitation of “a modified amino acid that is suitable for chemical conjugation”.
The rejection of claims 7 and 14 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. Applicants amended the claims to remove the limitation encompassing “other cell surface immune regulatory molecules”, and therefore resolves the indefiniteness of selecting from a “group consisting of” which includes an open-ended group of “other cell surface molecules”.
The rejection of claim 11 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. Applicants amended claim 11 to recite wherein “at least” one antibody is selected for mutation, and wherein “at least” one antigen binding arm comprises the substituted amino acid. As claim 11 is drawn to a multi-specific antibody, it further limits the monospecific antibody construct of claim 1.
Claim Rejections – Maintained
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.
Claims 4-5 and 9-10 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 4 recites “wherein the substituted amino acid residue occurs at an amino acid residue corresponding to : (3) residue 119 or 120 of SEQ ID NO: 9, 10, 11 or 12; or (4) residue 121 or 124 of SEQ ID NO: 13 or 14.” The claim is referring to claim 3, whereby a cysteine residue or a lysine residue, which is conjugated to a fatty acid, is substituted into the innate antibody domain sequence. However, the reference SEQ ID NOs do not comprise the length, in total residues, for which the claimed amino acid substitution are referencing. For example, SEQ ID NO: 9 is 103 residues in total length; none of SEQ ID NOs: 9-12, referring to the CH1 domain, have more than 105 total residues, as listed. See specifications, Table 1, pg. 65. Thus, the required amino acid substitution, for conjugating the fatty acid, cannot occur at residues 119 or 120 of SEQ ID NOs: 9-12, as those residues are not defined in the listed sequences. Similarly, SEQ ID NOs: 13 and 14, referring to the CL domain, have no more than 107 total residues as listed. Thus, the amino acid substitution cannot occur at residues 121 or 124, as those residues are not defined in the sequences. The specifications disclose that antibodies comprising a T120C or S119C substitution in the CH1 region were produced, and thus the substitutions within the CH1 domains are functional (see Table 3, pg. 66). However, claim 4 fails to particularly point out and distinctly claim the subject matter of the invention, as the numbering system seems to include more than the total residues of any one of SEQ ID NOs: 9-12. Thus, it is unclear where the numbering system begins, or more particularly, which T or S amino acid residues of the CH1 domain of SEQ ID NOs: 9-12, or the CL domain of SEQ ID NOs: 13-14, the claim is referring to. That is, it is unclear to the skilled artisan which substituted T or S amino acid residues, within SEQ ID NOs: 9-14, would read on the limitations of instant claim 4. As the metes and bounds of the claim are unclear, claim 4 is rejected for indefiniteness.
Similarly, claim 5 recites a substitution corresponding to “(3) a T120C substitution of SEQ ID NOs: 9, 10, 11 or 12.” It is unclear which T120C substitution is made when the listed, corresponding sequences have no more than 105 residues. Claim 9 similarly recites the residue corresponding to “(3) residue 119 or 120 of SEQ ID NO: 9, 10, 11 or 12; or (4) residue 121 or 124 of SEQ ID NO: 13 or 14”; which suffers from the same issue of indefiniteness. Claim 10, sub-sections (5-7), recite a monoclonal antibody comprising a T120C substitution in one of SEQ ID NOs: 9-12; yet none of the listed SEQ ID NOs are greater than 105 residues in length. Thus it is unclear which T residue in any one of SEQ ID NOs: 9-12 is being substituted with a cysteine residue. As the metes and bounds of claims 5, 9 and 10 are unclear, claims 5, 9 and 10 are rejected for indefiniteness.
Claims 5 and 10 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.
Further regarding claims 5 and 10; claim 5 recites a “K64C” substitution of SEQ ID NO: 1. SEQ ID NO: 1 is 119 amino acid residues in length, and lists a K at position 63, an F at position 64, and a K at position 65. Thus, it is unclear which residue a “K64C” substitution in SEQ ID NO: 1 refers to. It is unclear if the claim is drawn to a K63C substitution, a K65C substitution, or a F64C substitution. As the metes and bounds of the claim are unclear, claim 5 is rejected for indefiniteness. The same issue of indefiniteness is repeated in claim 10(1), which comprises a “K64C” substitution in SEQ ID NO: 1; whereby it is unclear if the substitution is to be made at position K63, F64 or K65. Further, as claim 10 is being interpreted as being drawn to a polypeptide comprising any subsequence of the reference SEQ ID NO (see claim interpretation above), it is also unclear what the amino acids of residues 63-65 of SEQ ID NO: 1 are for a skilled artisan when any subsequence (i.e. any 3 consecutive amino acid residues of SEQ ID NO: 1) is being claimed. Thus, claim 10 is also rejected for indefiniteness. Note that claims 4 and 9 recite a substitution at position “64” of SEQ ID NO: 1; this is interpreted by the examiner to refer to an F64 substitution.
Response to Arguments
Applicant's arguments filed 12/2/2025 have been fully considered but they are not persuasive. Applicants amended claims 4 and 9 to indicate that the amino acid substitutions in the VH and VL regions are numbered according to Kabat numbering, and the amino acid substitutions in the CH1 and CL regions are numbered according to EU numbering. Applicants contend that as the specifications and drawings depict the numbering scheme according to Kabat or EU numbering, the skilled artisan would understand which residues are encompassed by the specific substitutions required, and thus the claims are clear and definite (remarks, pg. 12, para. 3).
The examiner does not find the amendments sufficient nor the arguments persuasive. While the specifications and drawings may depict the Kabat or EU numbering scheme, the rejection is not for lack of descriptive support, but rather for lack of clarity, or particularly pointing out and distinctly claiming the subject matter. For example, claim 5 recites a “K64C substitution of SEQ ID NO: 1”; yet the 64th residue of SEQ ID NO: 1 is not a K. This is mis-leading language. The claim directly points the artisan to SEQ ID NO: 1, yet contends that the artisan should look to the art to renumber SEQ ID NO: 1 based on an alternative numbering scheme. Thus, the Kabat numbering of the antibody component, described in the specifications, is a different sequence numbering scheme than that of the SEQ ID NO directly referenced in the claim. Thus it is unclear to the artisan which, of two differently numbered amino acid sequences, the 64th residue is referring to. Therefore the metes and bounds of the claim are unclear. If the applicants intend for the substitution to occur at the 64th residue in reference to the Kabat numbering of the antibody component, then that should be incorporated, a priori, into the submitted sequence listing and claims, whereby the subject residue of the reference SEQ ID NO: is correct. That is, in this example, the claim should be drawn to the 65th residue of SEQ ID NO: 1, which may correspond to the 64th residue of an antibody structure numbered according to Kabat numbering, but is definite with regard to the claimed SEQ ID NO. However, in this case, the 64th residue of SEQ ID NO: 1 and the 64th residue of SEQ ID NO: 1 renumbered according to Kabat numbering, are different residues. Thus the claim is not definite. This is also true for each of the other mis-numbered SEQ ID NOs referenced in the rejections above. If the residue of the SEQ ID NO directly referenced in the claim is not the same as the residue of the structure re-numbered according to the Kabat, or EU, numbering scheme, then the claims are directing the artisan to two different residues, which creates confusion in interpreting the claims with regard to distinctly and particularly pointing out the limitations of the claims. Thus, the rejections are maintained.
Further, claim 10, uses the language of “a polypeptide sequence of SEQ ID NO: 1”, which is therefore interpreted as comprising any polypeptide subsequence, which may be only 2-3 amino acids in total length of shared similarity (see claim interpretation section above). Thus, it is necessary for the 64th residue to be clearly defined, as any VH having any sequence with a “K64C” substitution, and 2-3 common amino acid residues anywhere else in the VH sequence would be prior art over the antibodies of claim 10, as currently written. Examiner suggests that claim 10 be amended to distinctly claim “the polypeptide sequence of SEQ ID NO” such that the claimed sequences require the total sequence, including the substitution, of the referenced SEQ ID NO. Nonetheless, without distinctly identifying which residue of the corresponding SEQ ID NO comprises the specific substitution, it is unclear which 2-3 amino acid sub-sequence within the various VHs, VLs and CH1s known in the art would, or would not, be infringing on the claim. Thus, the rejections for failing to distinctly claim the subject matter of claim 10 is maintained as it results from the same issues in claims 4-5 and 9.
Claim Rejections - 35 USC § 112-maintained
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.
Claims 1-3, 6-8, 11-19, 20, 22, 25, 27-33 and 35-38 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 7 depends from claims 1 and 6. Claim 1 broadly recites an antibody, comprising a substituted amino acid in the VH or VL, wherein the substituted amino acid is conjugated to a fatty acid. Claim 6 recites whereby the antibody of claim 1 is an anti-immune cells modulator (ICM); and claim 7 recites wherein the ICM is selected from the group consisting of CD3, CD27, CD28, CD40, CD122, OX40, CD16, 4-1BB, GITR, ICOS, CTLA-4, PD-1, LAG-3, TIM-3, TIGIT, VISTA, SIGLEC7, NKG2D, SIGLEC9, KIR, CD91, BTLA, NKp46, B7-H3, SIRPα and other cell surface immune regulatory antigens. None of claims 1 or 6-7 identify which residues in the VH or VL of the species may be amendable for substitution with an alternative amino acid residue which is conjugated to a fatty acid, and yet maintain binding to the target antigen. Similarly, claim 14 depends from claims 1, 11, 12 and 13; whereby claims 11-13 refer to the antibody of claim 1, wherein the antibody is bi-specific, or multi-specific, and one arm of the antibody is directed to an ICM. Claim 12 identifies that the substituted amino acid residue which is conjugated to a fatty acid may occur in either the Ab1 arm, which is the ICM binding arm according to claim 13, or the Ab2 arm. Claim 14 identifies the same Markush group of ICM binding antibodies, wherein the fatty acid-conjugated amino acid may be substituted, within the VH or VL, or within 20 residues of the VH or VL. None of claims 1 or 11-13 identify which residues in the VH or VL of the species may be amendable for substitution with an alternative amino acid residue which is conjugated to a fatty acid, and yet maintain binding to the target antigen. The VH and VL domains of antibodies are each generally > 100 amino acid residues in length, and each comprise 3 CDRs which impart the binding specificity and affinity of the binding domain of the antibody. Thus, as each ICM antibody species listed in claims 7 and 14 (or any generic antibody species of claim 1) comprises > 200 amino acid residues, whereby any one (or more) of the residues may be substituted with an alternative amino acid conjugated to a fatty acid, the claims encompass a genus of each ICM listed (or alternatively any antibody species of claim 1), whereby the genus comprises a substituted amino acid conjugated to a fatty acid, at any one or more of at least 200 residues, and still maintains binding to its target antigen. That is, there are at least 200 possible anti-CD3 variants, there are at least 200 possible anti-CD27 variants, there are at least 200 possible anti-CD28 variants, etc., which are encompassed in the claims. Further, as the amino acid substitution(s) may occur within a CDR region, each genus comprises unidentified CDRs of the ICM binding antibodies having a CDR cysteine residue substitution.
In support of the claimed genuses of modified ICM antibodies, the specifications disclose only variants of an anti-CD3 (see example 1, pg. 62; pg. 64, para. 00220, line 1). Two different anti-CD3 antibodies were used, comprising the VH and VL of SEQ ID NOs: 1 and 2, respectively, or the VH and VL of SEQ ID NOs: 27 and 28, respectively. Both anti-CD3 antibody species comprise the same CDRs (see Table 1 and Table 2, pg. 65). Table 3 displays up to 70 candidate variants of the CD3 antibodies, wherein a cysteine residue was substituted in place of the native amino acid residue; 19 of the 70 candidate residues were tested and demonstrated to maintain > 50% binding to CD3 compared to wild type anti-CD3 antibodies. Of the 19 specific cysteine residue substitutions which maintained binding, 4/9 cysteine residue substitutions in the VH occurred within the CDRs, and 5/6 cysteine residue substitutions in the VL occurred within the CDRs; the other 4 cysteine residues substitutions occurred in the CH1 or CL regions. At least one variant, LC_S31C, lost significant binding activity after cysteine knock-in, and that substitution occurred within the CDR1 of the VL (pg. 67, para. 00225; Fig. 3). Thus, it is clear from the examples using anti-CD3 antibodies that only a select set of residues are amendable for substituting a cysteine residue, that some of the amendable residues are located within antibody CDR regions, while other residues, including alternative residues within the CDR, are not amendable to cysteine substitution and do not maintain binding to the target antigen after such substitutions. Therefore, the specific residues amendable for substitution are determined via experimentation, and the results are unique for the antibody species. For example, a comparison of the VH and the VL of the CD3 antibody of Example 1 (instant SEQ ID NOs: 1-2) to the VH and VL of an alternative ICM of claims 7 or 14, an anti-CD27 antibody of Eenennaam et al., (US 2013/0183316) SEQ ID NOs: 3-4, shows that the VH and VL amino acid sequences of the instant CD3 antibody and those of an alternative anti-CD27 antibody are quite different in amino acid residue sequence. Further, as seen in Figure 1 (below), different antibodies targeting different antigens have unique CDRs, which have unique amino acid sequences. Thus, the specific residues of the instant CD3 antibody that may be amendable to a cysteine substitution, hereby the antibody maintains binding to the target antigen, would not be the same residues of an alternative antibody which has specificity for an alternative target antigen.
Thus, the representative examples only address select embodiments of a genus of variant CD3 antibodies comprising a substituted cysteine residue conjugated to a fatty acid; the specifications do not provide any examples, nor guidance, as to which residues may be mutated to a cysteine in any of the alternative genuses of variant ICMs of claims 7 and 14.
[AltContent: textbox (Figure 1: Comparison of the VH (top) and VL (bottom) of an anti-CD3 antibody to that of an anti-CD27 antibody of US 2013/0183316. Instant anti-CD3 CDRs are highlighted with red boxes.
[img-media_image1.png]
[img-media_image2.png])]
Regarding the state of the art, it is known in the art that the antigen binding domain of an antibody requires the 6 complementarity determining regions (CDR) of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). However, the structure-to-function correlation continues to be highly unpredictable. For example, Chen et al., (1992) teaches that a single amino acid substitution in the VH CDR2 of PC-specific T15 antibody could increase, decrease or ablate binding the target antigen (abstract, Fig. 3), and this occurred in an unpredictable manner based on which residue was mutated. Similarly, a single point mutation in the heavy chain CDR3 region of the high affinity anti-VEGF antibody G6.31, could in some cases enhance, or otherwise completely ablate binding to the target antigen, and this also occurred in an unpredictable manner (Koenig et al., PNAS, 2017). That is, only screening each mutation individually provided insight as to the resulting changes in functionality. In some cases this extends even beyond the CDRs. Within the framework regions, Koenig et al. (PNAS, 2017) teaches that various amino acid point mutations can increase or decrease binding or neutralization capacity. Some amino acid residues are more tolerant to substitution, while other “conserved” residues are less tolerant, such that a single amino acid substitution may defunctionalize the antibody (pg. E487, Fig. 1). Thus, while antibodies share certain characteristics such as Fc regions or hinge regions, these regions are not correlated with the binding function of the antibody. Conversely, the hyper-variable regions, comprising the complementary set of 6 CDRs, are well established in the art as the portion of the binding regions which impart the specificity of the antibody; and yet, there is no way to look at an amino acid sequence and envision, a priori, whether the combination of six CDRs will bind a particular epitope, even when the CDRs are highly related, without teachings of the basic shared amino acid residues that are sufficient to impart functional binding across all variants. Further, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg. 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg. 11). Thus, when claiming a genus of antibodies based on their binding to a common target, the representative examples must cover the full scope of structural variabilities which encompass all species variants that would bind the target.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants do not provide any variants of the alternatively claimed ICM antibodies, in which cysteine residue substitutions were made, which were reduced to practice and demonstrated functionality. Applicants also do not identify the shared structural properties of any CDR residues that would define the genus beyond the desired functionality. Currently the essential property of maintaining binding to the target antigen despite a single cysteine residue substitution are imparted by the specific set of residue substitutions to an anti-CD3 antibody, as described in Table 3, wherein specific residue substitutions may occur at select residues (but not others) within the CDR sequences. Specifically, the candidate residues for substitution with a cysteine residue conjugated to a fatty acid, whereby the antibody maintains binding to its target antigen, should be disclosed for each ICM that is being claimed. This lack of definition complicates the determination of the boundaries of the claimed genuses with regard to which, as of yet unidentified, species variants would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims.
“The purpose of the written description requirement is to ‘ensure that the scope of the
right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s
contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli
Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D.
Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description
requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed
invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir.
1991). See also MPEP 2163.04. Otherwise, the “claims merely recite a description of the
problem to be solved while claiming all solutions to it and … cover any compound later actually
invented and determined to fall within the claim’s functional boundaries- leaving it to the
pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli
Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
Applicants have not described the candidate residues, for substitution with a cysteine residue conjugated to a fatty acid and whereby the antibody maintains binding to its target antigen, for any of the ICMs of “CD27, CD28, CD40, CD122, OX40, CD16, 4-1BB, GITR, ICOS, CTLA-4, PD-1, LAG-3, TIM-3, TIGIT, VISTA, SIGLEC7, NKG2D, SIGLEC9, KIR, CD91, BTLA, NKp46, B7-H3, SIRPα and other cell surface immune regulatory antigens” of claims 7 and 14. Thus, applicants fail to show they had possession of the claimed genus, nor do applicants describe any shared structural feature common to all species of the claimed genuses that would necessarily impart the desired properties of the claimed embodiments. Therefore, claims 1, 6-7 and 11-14 are rejected for lack of adequate written description. As claim 1 is rejected for lack of adequate written description, claims 2-3, 15-17, 20, 22, 25, 27-33 and 36-38, which depend from claim 1 but fail to rectify the lack of descriptive support, are also rejected.
Regarding claims 8 and 18-19; while claim 8 requires the antibody to comprise the VH and VL CDRs of SEQ ID NOs: 3-8, respectively, or 33-38, respectively; claim 1 recites that the amino acid residue conjugated to a FA may be substituted at any position within a 20 amino acid distance of the VH or VL. Koenig et al. teaches that some residues of the framework regions are intolerant to amino acid substitution, such that a single mutation to a critical FR residue de-functionalizes the antibody, whereby it no longer binds the target antigen, as described above. Thus, requiring that the antibody comprises the CDRs of SEQ ID NOs: 3-8 or 33-38, does not sufficiently describe which positions, within the VH or VL, or within 20 amino acid residues of the VH or VL, are amendable to substitution with an amino acid residue conjugated to a fatty acid, and which still maintains binding to the target antigen. There is lack of descriptive support for any amino acid substitution which occurs outside of the CDRs but within 20 amino acids of the VH or VL, such that the antibody maintains binding to the target antigen. Claim 18 is interpreted to require only “a polypeptide sequence” of the listed VH and VL; see claim interpretation section above. Thus, the polypeptide sequence of the CDRs would be all that are required, and the substitution of an amino acid residue conjugated to a fatty acid may occur at any other location within the VH or VL, or within 20 amino acid residues of the VH or VL. Thus, there is a lack of descriptive support for any amino acid residue substitution which occurs outside of the CDRs, but within 20 amino acid residues of the VH or VL, and whereby the antibody maintains binding to the target antigen. Thus, claims 8 and 18 are rejected for lack of adequate written description support. As claim 19 depends from claim 18, but does not rectify the lack of descriptive support, claim 19 is also rejected.
Response to Arguments
Applicant's arguments filed 12/2/2025 have been fully considered but they are not persuasive. Applicants traverse the rejection and highlight that instant claim 1 requires that the antibody, or antigen binding fragment thereof, which comprises the amino acid substitution whereby the FA is conjugated to the antibody “still binds to the target antigen,” (remarks, pg. 16, para. 1). Applicants highlight that the test for compliance with written description requirement includes wherein the specification must describe an invention understandable to the skill artisan and show that the inventor actually invented the invention claimed (remarks, pg. 16, para. 2). Applicants contend that the key feature of the invention is conjugating a FA to the antibody, whereby the biological activity of the antibody is downregulated, and that “other” features, such as the position of the conjugation, antibody target, will not affect the achievement of the technical result of the instant invention (remarks, pg. 16, para. 3). Applicants contend that it is not necessary to exemplify every single potential antibody encompassed by claim 1; and that Table 3 in the examples provides 70 potential amino acid substitution for an anti-CD3 antibody. Thus, applicants suggest that a person skilled in the art would have “a plan” to determine amino acid substitutions for any antibody, including those with target specificity to the 25 different antigen targets listed in claims 7 and 14; and thus the artisan would also have a description of the experiments to test the variant antibodies created to determine if the variants have the functional features outlined in claim 1 (remarks, pg. 17, para. 1).
In response, the examiner acknowledges the requirement for written description, that the specification must describe an invention understandable to the skill artisan and show that the inventor actually invented the invention claimed. In this case, the examiner rejected the claims for lack of written description because the specifications do not describe the full scope of the claimed invention, do not provide a representative number of embodiments of the invention as claimed, and thus do not show possession of the claimed invention across the full scope of the claims. Applicants contend that the key feature of the invention is its functionality, and thus only antibody variants that meet the functional description would be within the scope of the claims. The examiner points out that for examination of a product (i.e antibodies), the key feature of the invention is the structure of the product, from which the desired function naturally flows. While the desired function can be read into the claims, the function (or properties) of the product are inherent to the structure of the product. The written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. For example, the courts held that “disclosure of an antigen fully characterized by its structure, formula or physical properties does not, without more, provide adequate written description of an antibody claimed by its binding affinity to that antigen (Amgen v. Sanofi, 872, F.3d 1367 (Fed. Cir. 2017)). This highlights that the desired functionality of an antibody does not adequately describe the structure of any and all antibody variants that would meet the desired functionality; rather, the structure of the invention itself, the antibodies, must be described. A correlation between structure and function may be described, wherein all of the claimed embodiments have a shared structural feature which imparts the claimed function. In the case of instant claim 1, the variant antibodies, comprising the conjugated FA, must “still bind to the target antigen”. However, claim 1 encompasses any antibody that binds to any target; claims 7 and 14 limit the antibodies to those that bind CD3, CD27, CD28, CD40, CD122, OX40, CD16, 4-1BB, GITR, ICOS, CTLA-4, PD-1, LAG-3, TIM-3, TIGIT, VISTA, SIGLEC7, NKG2D, SIGLEC9, KIR, CD91, BTLA, NKp46, B7-H3, SIRPα. It is immediately clear to a skilled artisan that antibodies which bind CD3 and antibodies which bind CD27 will not have a shared structural feature that imparts their functionality of specifically binding to their respective antigens; the target binding is encoded, in large part, by the CDRs, and the CDRs of each antibody are unique and determine the specificity and affinity of binding to their target antigens, as described above. The claimed antibodies require conjugation to a FA, whereby a residue in the structure of the antibody is substituted to a cysteine or a lysine for conjugating the FA. As described above, it is known in the art that a single point mutation in the structure of an antibody can defunctionalize the antibody, whereby it no longer binds its target antigen; and the location of these critical residues will be different for different antibody species. Regarding only the anti-CD3 antibodies of the invention, the specifications describe 70 different amino acid positions that may be mutated; however a number of these positions are located within the CDRs, which are critical for maintaining binding functionality to CD3. The examiner highlighted one variant embodiment, LC_S31C, which lost significant binding activity after cysteine knock-in, and that substitution occurred within the CDR1 of the VL (specs., pg. 67, para. 00225; Fig. 3). Thus, the specific amino acid residue which is being substituted with a cysteine or lysine, is critical in assessing whether the antibody will maintain the required binding to the target antigen; particularly if that residue is within a CDR. The specific anti-CD3 antibody variants described required experimentation in order to determine 70 different candidate residues for mutation, thus applicants are claiming a genus of variant anti-CD3 antibodies, comprising 70 alternative species (or 140 species if the substitution can be either cysteine or lysine), whereby some amino acid substitutions defunctionalize the antibody. As anti-CD27 antibodies (or any other antibody) will have a different structure from anti-CD3 antibodies, the number of, and specific locations of, the amino acid residues that may be substituted to a cysteine or lysine will be different. Thus, as described above, applicants are claiming a genus of anti-CD27 antibodies, which may be entirely different from the genus of anti-CD3 antibodies with regards to candidate residues for substitution with a cysteine or lysine conjugated to a FA; and this applies for each antibody species listed in claim 7, whereby each target antigen claimed encompasses a separate genus of variant species with a different amino acid residue mutated. This also applies to two different antibodies that target the same antigen; if they have a different basal structure, then the number of, and location of, candidate residues for amino acid substitution will be different between each antibody species. That means that for each and every antibody species claimed, the specifications need to describe which amino acid residues, specific for that antibody species, can be substituted with a cysteine or lysine residue and still maintain binding to the target antigen. As should be clear, where claim 1 is drawn to any antibody, applicants are claiming an infinite number of variant antibodies, each with a unique structure, and with no shared structural commonality across all embodiments which imparts the property of “still maintains binding to the target antigen”. In terms of the number of representative examples of the enormous scope of the claimed invention, applicants do not disclose which amino acid residues can be mutated in any antibody species other than a single species of an anti-CD3 antibody. Thus the specifications suffer from a significant lack of written description over the scope of the claimed invention by not providing the necessary structures of the claimed embodiments which impart the desired function.
Regarding applicant’s contention that a skilled artisan would have “a plan” to determine amino acid substitutions for any antibody, and the teachings of the requisite experiments to run in order to identify such positions. This comment underscores the lack of written description; if the artisan would have to use the plan and run the experiments to determine the suitable amino acid residues for substitution across any unique antibody species, then the artisan is “inventing” the invention. Determining the specific amino acid residues that may be mutated to a cysteine or lysine, in any particular antibody species, whereby the variant antibody is conjugated to a FA and maintains the desired properties of claim 1, including wherein the antibody maintains binding to its target antigen, is necessary to describe the structure of the claimed invention. Applicants who are in possession of the claimed invention can disclose the structure; without adequate disclosure of the structure, applicants are deemed to not be in possession of the claimed invention. As described in the rejection above, “The purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04. Otherwise, the “claims merely recite a description of the problem to be solved while claiming all solutions to it and … cover any compound later actually invented and determined to fall within the claim’s functional boundaries- leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
Applicants have not described, nor disclosed, a representative number of species, nor a structure to function correlation, across the vast majority of the variant antibody species claimed. Applicant’s contention that the invention is being claimed by functionality is not sufficient to describe the structure of the invention. Applicant’s contention that a plan, and accompanying experiments, are available to a skilled artisan to do the work necessary to determine the specific amino acid residues that may be mutated across an infinite number of structurally distinct antibodies, whereby any single amino acid substitution at a critical residue would de-functionalize the antibody, is not sufficient to describe possession across the enormous scope of the claimed invention. Applicant’s arguments are unpersuasive, and the rejection over the lack of adequate written description is maintained.
Claim Rejections - 35 USC § 102- maintained, amended
The following rejection is maintained and amended. The amendments were necessitated by applicant’s amendments to instant claims 1 and 7.
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.
Claims 1-3, 6, 20 and 22 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Pessi et al., (from IDS of 10/28/2022, cite No. 7; US 2013/0150563; published 6/13/2013).
Pessi teaches novel lipid-conjugated antibodies for use in the treatment or the preventions of diseases including cancer (abstract). Pessi teaches there is a need for improving the binding efficiency of antibodies against cell surface displayed proteins by building into the antibody the ability to bind the lipid-membrane, representing a general approach for generating more effective and better tolerated therapeutic and prophylactic agents (pg. 1, para. 0006). Pessi teaches novel and improved antibodies with excellent pharmaceutical properties and considerably improved biological potency, by modifying the antibody capable of specifically binding their respective epitopes to additionally bind the plasma membrane of a target cell, such as a cancer cell. Pessi teaches the modification includes covalently linking a lipid, optionally via a linker, to a therapeutic antibody (pg. 1, para. 0008). Pessi teaches the lipid may be linked to an amino acid of an antibody domain selected from the VL, VH, CL or CH1 (pg. 1, para. 0009). Pessi teaches that antibodies that are modified by linking them to a lipid, exhibit an improved partition ratio between antibody in the extracellular medium and antibody bound to the lipid membrane, such as localization to the lipid-raft microdomains of the plasma membrane, where they can be more effective; and whereby they may have improved cellular uptake of the antibody into a target cell (pg. 4, para. 0039). Pessi teaches that preferably the lipid is a sphingolipid (pg. 6, para. 0075).
Pessi teaches the lipids may be covalently linked to the amino acid by a linker, preferably the lipid is covalently linked to a cysteine residue of the antibody (pg. 8, para. 0081), whereby the linker is attached to the sulphur moiety of a cysteine amino acid that naturally occurs in the antibody or has been introduced into said antibody via mutagenesis (pg. 8, para. 0083). Pessi teaches, for example, a cholesterol moiety is attached to the antibody via a thioether linkage with the thiol group of cysteine residue in the antibody (pg. 13, para. 0135). Pessi teaches the linkers may contain a polymeric spacer unit (pg. 7, para. 0079), and provides examples using a linker comprising PEG4 (pg. 15, example 4, Synthesis of Bromoacetyl-PEG4-Cholesterol; para. 0141). Pessi teaches mutations may be made to the antibodies whereby the light and heavy chain comprise one or more amino acid substitutions, such that a cysteine residue may be substituted into the variable region (pg. 10, para. 0088). Pessi teaches a specific example, whereby the anti-ErbB2 mAB Trastuzumab features a substitution of the Thr in position 20 with a Cys (i.e. T20C) in the light chain, for attaching a cholesterol (pg. 19, para. 0169). Pessi teaches another example embodiment wherein the light chain of Rituximab is mutated for lipid conjugation, comprising a T20C substitution in the light chain (pg. 4, Table 2, SEQ ID NO: 36).
Regarding claims 1-3; Pessi teaches an isolated monoclonal antibody, with a VH and a VL, wherein an amino acid in the VL is substituted with an cysteine amino acid, whereby the cysteine amino acid is conjugated to a lipid (e.g. sphingolipid), which comprises a fatty acid, and whereby the antibody maintains binding to the target antigen. It is known in the art that most lipids, including sphingolipids, comprise fatty acids and that fatty acids bind albumin as their primary mechanism of transport in the blood. Thus, as the invention of Pessi anticipates the structure of the antibody claim 1, wherein the antibody is conjugated to a fatty acid, the invention of Pessi also anticipates the inherent properties of the antibody-fatty acid conjugate whereby the fatty acid conjugated to the antibody or antigen binding fragment thereof is capable of binding albumin, wherein the binding of albumin to the fatty acid results in a partial or a complete blocking of the binding between the target antigen and the antibody. Thus, the invention of Pessi anticipates instant claims 1-3.
Regarding claim 6; Pessi teaches a modified Rituximab antibody (see Figure 17), comprising a cysteine substitution at either residue 20 or 22. Rituximab is an anti-CD20 antibody; and CD20 is highly expressed on the surface of, and is a modulator of activity of, B cells, which are immune cells. Thus, Rituximab qualifies as a cell surface anti-immune cell modulator (ICM); and the invention of Pessi anticipates instant claims 6. Claim 7 has been removed from the rejection in view of applicant’s amendment to claim 7, whereby CD20 is not one of the selected ICMs to which the invention is limited.
Regarding claims 20 and 22; Pessi teaches the sphingolipid of the invention comprises fatty acids with 14 carbons (see figure, pg. 6, para. 0075). Thus, Pessi anticipates instant claim 20. Pessi teaches the linker may be PEG4, as described above (see pg. 16, para. 0141); thus Pessi anticipates claim 22.
Claim Rejections - 35 USC § 103- maintained, amended
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 6-8, 11-15, 20, 22, 27-33 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Pessi et al., (from IDS of 10/28/2022, cite No. 7; US 2013/0150563; published 6/13/2013) and Dixit et al., (WO 2015/006749; published 1/15/2015).
The reasons why claims 1-3, 6, 20 and 22 are anticipated by Pessi are described above. Specifically, Pessi teaches making an amino acid substitution in the light chain of the anti-20 antibody Rituximab, whereby the substitution is a cysteine residue conjugated to a lipid. However, Pessi does not teach wherein the antibody is bispecific or multispecific.
Dixit et al. teaches bispecific antigen binding constructs which bind to CD3 and CD20 (abstract). Dixit teaches bispecific antibodies capable of targeting T cells to tumor cells, comprising a first antigen binding polypeptide construct which monovalently and specifically binds a CD20 antigen and a second antigen binding polypeptide construct which specifically binds a CD3 antigen (pg. 2, para. 0006). Dixit teaches that CD20 is considered a B cell tumor-associated antigen (pg. 26, para. 00100). Dixit teaches the bispecific construct comprises a CD3 antigen binding polypeptide, wherein the VH and VL regions are derived from a CD3 specific antibody selected from a group including OKT3 or 12F6, among others (pg. 25, para. 0097). Dixit teaches embodiments which were prepared and tested (pg. 67, para. 00248; Table 1); for example, V1821, which comprises a common light chain of the CD20 antibody Rituximab, and a heavy chain of the CD3 antibody 12F6. Dixit teaches the full-size molecule does not require using a common light chain as in V1821, and may instead use the corresponding light chains for anti-CD3 and anti-CD20 (pg. 63, para. 00228). Regarding the anti-CD3 antigen binding domain of OKT3, Dixit teaches stabilized variant of OKT3 which comprises a C-to-S amino acid substitution in the HCDR3 domain (see Table ZZ; pg. 112, SEQ ID NO: 348). Thus, Dixit teaches the OKT3 LCDRs 1-3 of SEQ ID NOs: 343-345 and the HCDRs of SEQ ID NOs: 346-348, respectively. The VH of Dixit, corresponding to the VH of OKT3, of SEQ ID NO: 183 (pg. 105), wherein the CDR3 has the C-to-S substitution, comprises the VH CDRs of instant SEQ ID NOs: 3-5 with 100% amino acid sequence identity; and the VH sequence of Dixit has 100% sequence identity to the VH of instant SEQ ID NO: 1. The VL CDRs of Dixit SEQ ID NOs: 343-345 match the CDRs of instant SEQ ID NOs: 6-8 respectively (albeit with a different numbering scheme); and the VL of Dixit SEQ ID NO: 184 is 100% identical to instant SEQ ID NO: 2, and comprises the CDRs of instant SEQ ID NOs: 6-8 with 100% identity. Further, Dixit teaches an alternative OKT3 CD3 binder having the VH of SEQ ID NO: 227, which is 100% identical to instant SEQ ID NO: 27; and a VL of (Dixit) SEQ ID NO: 226 (pg. 107), which is 100% identical to instant SEQ ID NO: 28. Dixit also teaches a CH1 domain of SEQ ID NO: 202, which is identical to instant SEQ ID NO: 9 but lacking 5 amino acids at the C-terminal end. However, when the CH1 of Dixit is embodied in the full heavy chain construct, of SEQ ID NO: 200 (pg. 106), the full sequence of instant SEQ ID NO: 9 is embodied with 100% sequence identity. Dixit also teaches the kappa constant domain of SEQ ID NO: 199, which is 100% identical to instant SEQ ID NO: 13. Thus, Dixit teaches identical sequences for the VH domain of instant SEQ ID NOs: 1 and 27, for the VL domains of instant SEQ ID NOs: 2 and 28, for the CH1 domain of instant SEQ ID NO: 9 and for the kappa constant domain of instant SEQ ID NO: 13.
Taken together, Dixit teaches CD3/CD20 bispecific antibodies, whereby the CD3 binding domain is a variant of OKT3, comprising identical amino acid sequences to instant SEQ ID NOs: 1-2 or 27-28, and whereby the CD20 binding domain is from Rituximab; and wherein the Fab of each binding domain is used, such that the construct comprises a VH, VL, CH1, CL and Fc domain (see Fig. 1D for full size antibody format).
It would have been obvious to one of skill in the art to modify the CD3/CD20 bispecific antibody of Dixit to use the modified CD20 binding domain of Pessi, wherein the anti-CD20 light chain comprises a T-to-C substitution at residue 20, and wherein the substituted cystine residue is conjugated to a lipid, as taught by Pessi. One would have been motivated to do so given that conjugating a lipid to an anti-CD20 antibody would improve the functionality of the antibody at the plasma membrane surface expressing CD20, as taught by Pessi; and that a bispecific antibody co-targeting CD3 and CD20 would target T cells to the tumor, as taught by Dixit. There would have been a reasonable expectation for success given that the CD3/CD20 antibody of Dixit uses the antigen binding domain of Rituximab, and that the modified CD20 light chain, conjugated to a lipid, of Pessi, is also Rituximab. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claims 7 and 8, the combination bispecific antibody of Pessi and Dixit comprises a CD3 Fab of a variant OKT3 clone, wherein the anti-CD3 arm comprises the VH and VL of instant SEQ ID NOs: 1-2 or 27-28, respectively, and which comprises the CDRs 1-6 of instant SEQ ID NOs: 3-8 with 100% sequence identity. Thus, the combination of Pessi and Dixit make obvious instant claim 8, and wherein the ICM is CD3 of instant claim 7.
Regarding claims 11-15; the combination CD3/CD20 antibody of Pessi and Dixit is bispecific, comprising a first antigen-binding arm and a second antigen-binding arm, and comprises a substituted amino acid in the light chain of Rituximab, wherein the amino acid residue is substituted with a cysteine conjugated to a lipid, comprising a fatty acid; thus the combination of Pessi and Dixit makes obvious instant claims 11-12. The first antigen binding arm of the CD3/CD20 bispecific antibody of Pessi and Dixit, binds to an immune cell modulator, wherein the ICM is CD3; and the second antigen binding arm binds to CD20, which is a tumor associated antigen, as taught by Dixit. Thus the combination antibody of Pessi and Dixit make obvious instant claims 13-15.
Regarding claims 27-30; Dixit teaches isolated nucleic acids encoding the antibodies or antigen binding fragments (pg. 118, claims 29-30); vectors comprising the nucleic acids (pg. 118, claims 32-33); host cells comprising the vectors (pg. 118, claims 34-35); and pharmaceutical compositions comprising the antibodies (pg. 116, claims 17-20). Thus, the combination of Pessi and Dixit make obvious instant claims 27-30.
Regarding claims 31-33 and 35; Dixit teaches a method of treating cancer comprising administering the bispecific antibody, or the pharmaceutical composition comprising the bispecific antibody (pg. 116, claims 20-21). Dixit teaches wherein the cancer is non-Hodgkin’s lymphoma (pg. 117, claim 23). Dixit teaches a method of producing the bispecific antibody (pg. 117, claim 26), and by extension a method of producing a pharmaceutical composition comprising the antibody (pg. 116, claim 17). Thus, the combination of Pessi and Dixit make obvious instant claims 31-33 and 35.
Response to Arguments
Applicant's arguments filed 12/2/2025 have been fully considered but they are not persuasive. Regarding the 35 USC § 102 and 35 USC § 103 rejections, the applicants contend that as the previous claim 25 was not included in the previous rejections, the limitations of previous claim 25 were moved into amended claim 1, and claim 25 was canceled. Thus, applicants believe that claim 1, as amended, is not anticipated by or obvious over the Pessi, or the combination of Pessi and Dixit (remarks, pg. 17, paras. 3-6).
The examiner’s response is that the limitations of original claim 25 are drawn to the functional properties of the claimed product. MPEP 2112.01 teaches that when the structure recited in the reference(s) is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent. As Pessi teaches an antibody with an amino acid substitution within the VH or VL, or within a 20 amino acid distance of the VH or VL, whereby the substituted amino acid residue is cysteine conjugated to a lipid, which comprises a FA, whereby the FA binds to albumin, then the structure of Pessi anticipates the structure of the antibody of instant claim 1. Therefore, the properties of amended claim 1, whereby the FA conjugated to the antibody is capable of binding albumin and wherein the binding of albumin to the FA results in a partial or a complete blocking of the binding between the target antigen and the antibody, is inherent to the antibody of Pessi, as well as to the combination of Pessi and Dixit. Thus, the inclusion of limitations drawn to the features/properties of the antibody into claim 1 does not obviate the anticipation of the antibody by Pessi, nor the obviousness of the antibody over the combination of Pessi and Dixit. Applicant’s arguments are not found persuasive, and the rejections are maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 11-17 and 27-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 10-11, 13, 15-18 and 20-22 of copending Application No. 18/264029 in view of Pessi et al., (from IDS of 10/28/2022, cite No. 7; US 2013/0150563; published 6/13/2013) and Dixit et al., (WO 2015/006749; published 1/15/2015).
Application ‘029 claims a bispecific antibody wherein the H1L1 and H2L2 each comprise a charge pair mutation comprising a G166D/E in CH1 of H1 and S114K/R in CL of L1 and G166K/R in CH1 of H2 and S114D/E in CL of L2 (claim 1); wherein the two heavy chains H1 and H2 each comprise a CH1 region and a Fc region, wherein the VH regions have different amino acid sequences (claim 2); wherein H1 and H2 form a heterodimer (claim 3); wherein the bispecific antibody comprises an anti-immune cell modulator (ICM) antibody (claim 10); whereby the ICM is a CD3 (claim 11); and wherein the bispecific antibody is a CD3/DLL3 bispecific antibody (claim 13). App ‘029 also claims a nucleic acid encoding the antibody (claim 15); a vector comprising the nucleic acid (claim 16); a host cell comprising the vector (claim 17); and a pharmaceutical composition comprising the antibody (claim 18). App ‘029 also claims a method of treating cancer with a CD3 bispecific antibody wherein the cancer is non-Hodgkin’s lymphoma (claim 20); a method of producing the antibody (claim 21) and a method of producing a pharmaceutical composition (claim 22).
However, app ‘029 does not claim wherein the bispecific antibody has a substituted amino acid residue in the VH or VL, and wherein the substituted amino acid residue is a cysteine conjugated to a fatty acid.
The combination bispecific antibody of Pessi and Dixit is described above. Specifically, the combination bispecific antibody of Pessi and Dixit is a CD3/CD20 bispecific antibody, wherein a lipid, comprising a fatty acid, is conjugated to a cysteine amino acid which is substituted in at residue 20 of the CD20 VL of Rituximab. Further, Dixit teaches the bispecific constructs may be 1) a dual scFv format; 2) a hybrid format comprising a scFv and a Fab; or 3) a full antibody format comprising 2 Fabs and an Fc domain (see Figure 1). Dixit teaches the CD3/CD20 Fabs may comprise a CH1 domain of human IgG1 and the CL domain of human kapa light chain. For example see Dixit v1821, a full size CD3/CD20 mAb (pg. 71, Table 5), which comprises the CH1 domain of clone 1342 (SEQ ID NO: 202) and the kappa CL domain of clone 1335 (SEQ ID NO: 199), according to Table YY (pg. 86), and corresponding to amino acid sequences of Table YY2 (pg. 106). Thus Dixit teaches the CD3 and CD20 antigen binding domains may be coupled to a human CH1 domain and a human kappa CL domain in a full bispecific antibody format. Further, Dixit teaches the Fc domains may be heterodimers, wherein the IgG1 Fc chain A and chain B each comprise alternative residue substitutions that enhance their dimerization (see Table A, pg. 13).
It would have been obvious to one of skill in the art to modify the bispecific antibody of application ‘029 to comprise the CD3/CD20 binding domains of the bispecific antibody of Dixit and Pessi, wherein the anti-CD20 binding domain (Rituximab) comprises the cysteine conjugated to a lipid substitution at residue 20 of the VL. One would have been motivated to do so given that conjugating a lipid to an anti-CD20 antibody would improve the functionality of the antibody at the plasma membrane surface expressing CD20, as taught by Pessi; and that a bispecific antibody co-targeting CD3 and CD20 would target T cells to the tumor, as taught by Dixit. There would have been a reasonable expectation for success given that the CD3/CD20 bispecific antibodies of Dixit may be formatted in various alternative formats which may include incorporating the CD3 and CD20 antigen binding domains with a CH1 of human IgG1 and the CL of human kappa constant region. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Specifically, claims 1-3 of app ‘029, in view of Pessi and Dixit, make obvious the bispecific antibody of instant claims 1, 11-12 and 17. Claims 10-11 and 13 of app ‘029 in view of Pessi and Dixit, make obvious wherein the bispecific antibody targets an ICM, wherein the ICM is CD3, and wherein the second binding domain targets the tumor associated antigen DLL2, of instant claims 13-16. Claims 15-18 of app ‘029, in view of Pessi and Dixit, make obvious instant claims 27-30; and the methods of claims 20-22 of app ‘029, in view of Pessi and Dixit, make obvious instant claims 31-33.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 12/2/2025 have been fully considered but they are not persuasive. Regarding the double patenting rejection, the applicants contend that as the previous claim 25 was not included in the previous rejections, the limitations of previous claim 25 were moved into amended claim 1, and claim 25 was canceled. Thus, applicants believe that claim 1, as amended, is not obvious over the combination of application ‘029, Pessi and Dixit (remarks, pg. 18, paras. 1-2).
The examiner’s response is that the limitations of original claim 25 are drawn to the functional properties of the claimed product, and not the structural limitations. MPEP 2112.01 teaches that when the structure recited in the reference(s) is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent. As Pessi teaches an antibody with an amino acid substitution within the VH or VL, or within a 20 amino acid distance of the VH or VL, whereby the substituted amino acid residue is cysteine conjugated to a lipid, which comprises a FA, whereby the FA binds to albumin, then the structure of Pessi anticipates the structure of the antibody of instant claim 1. Therefore, the properties of amended claim 1, whereby the FA conjugated to the antibody is capable of binding albumin and wherein the binding of albumin to the FA results in a partial or a complete blocking of the binding between the target antigen and the antibody, is inherent to the antibody of Pessi, as well as to the combination of application ‘029, Pessi and Dixit. Thus, the inclusion of limitations drawn to the features/properties of the antibody into claim 1 does not obviate the obviousness of the antibody over the combination of application ‘029, Pessi and Dixit. Applicant’s arguments are not found persuasive, and the rejections are maintained.
Allowable Subject Matter
Some of the claims may comprise allowable subject matter. Specifically, as embodied in claim 18, the VH of SEQ ID NO: 15 is free of the prior art, and the CH1 of SEQ ID NO: 20 is free of the art, when each sequence requires 100% amino acid sequence identity.
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 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 JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642