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 4/14/2026, are acknowledged and entered into the record. Applicants amended claims 4, 9-10, 18-19 and 30 in the remarks of 4/14/2026.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/14/2026 has been entered.
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Claim Rejections and Objections-Withdrawn
The objection to claims 30 is withdrawn in view of applicant’s amendments to the claims to correct the informality.
Claim Rejections - 35 USC § 102
The rejection of claims 1-3, 6, 20 and 22 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as being anticipated by Pessi et al., (from IDS of 10/28/2022, cite No. 7; US 2013/0150563; published 6/13/2013), is withdrawn. Applicant’s contention that Pessi does not teach an embodiment that is sufficiently identical, and therefore cannot anticipate, is found persuasive.
Claim Rejections - 35 USC § 103
The rejection of claims 1-3, 6-8, 11-15, 20, 22, 27-33 and 35 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cite No. 7; US 2013/0150563; published 6/13/2013) and Dixit et al., (WO 2015/006749; published 1/15/2015), is withdrawn. Applicant’s contention that Pessi does not teach an embodiment that is sufficiently identical, and therefore cannot anticipate, is found persuasive.
Double Patenting
The rejection of claims 1, 11-17 and 27-33 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), is withdrawn.
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. 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 4/14/2026 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 “the numbering does not refer to the specific number of the amino acid residue as indicated in SEQ ID NOs: 1-2, 9-14, or 27-28 in the sequence listing, but rather the Kabat numbering of the VH and VL regions and EU numbering of the CH1 and CL regions,” (remarks, pg. 11, para. 1). Applicants go on to describe internet computer programs through which a skilled artisan may input the sequences in order to determine how the residues recited in the claims actually map to referenced SEQ ID NOs recited in the claims (remarks, pg. 11). Regarding claims 5 and 10, applicants contend that a skilled artisan may input the sequence of SEQ ID NO: 1 into an internet computer program whereby, using the selected kabat numbering scheme, the computer program will demonstrate where the lysine residue should be (remarks, pg. 12, para. 2).
The applicant’s contention that “the numbering does not refer to the specific number of the amino acid residue as indicated in SEQ ID NOs: 1-2, 9-14, or 27-28 in the sequence listing, but rather the Kabat numbering of the VH and VL regions and EU numbering of the CH1 and CL regions”, is the reason why the claims are rendered indefinite. The claims cannot recite a specific residue of a specific reference SEQ ID NO, whereby the specified residue does not exist in the referenced SEQ ID NO, and contend that the skilled artisan must use an internet computer program to translate what the intended residue for mutation is supposed to be. The claims are rejected for not particularly pointing out and distinctly claiming the subject matter. It is misleading to claim a reside substitution in a referenced sequence only to argue that it is not the residue of the referenced sequence, but rather the residue of a different sequence which may be translated to the corresponding residue of the referenced sequence by a skilled artisan with the help of an internet computer program. The claims must particularly and distinctly claim the subject matter. For example, if a claim reads “residue 120 of SEQ ID NO: 9”, then it must refer to the 120th residue of the sequence of SEQ ID NO: 9. If applicants intend for the mutated residue to be translated from a Kabat (or alternative) numbering system of an antibody fragment or particular domain which relates to the sequence of, for example SEQ ID NO: 9, then applicants should perform the translation themselves, identify the corresponding residue in SEQ ID NO: 9, and amend the claims such that the claim recites the specific residue of the referenced sequence (i.e. SEQ ID NO: 9) that is intended for mutation. Otherwise, multiple interpretations of the specified residue exist, and the claims are rendered indefinite. This is true also for claims 5 and 10 which refer to a specific substitution, for example, a K64C substitution of SEQ ID NO: 1, even though there is not a K at residue position 64 of SEQ ID NO: 1 to be substituted. This is contrary to “particularly pointing out and distinctly claiming” the subject matter. Applicant’s remarks seem to suggest the artisan must rely on an alternative internet program interpretation to decipher the correct amino acid residue of SEQ ID NO: 1 in which the K-to-C substitution should be made; and counters the most reasonable interpretation of the phrase “a K64C substitution of SEQ ID NO: 1”, as recited in the claim. Applicant’s amendments are insufficient to resolve the indefiniteness, and applicant’s arguments are not found persuasive. The rejections are maintained.
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, 11-17, 20, 22, 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 antibodies, for each ICM listed (or alternatively any antibody species of claim 1), whereby each genus comprises alternative variant species comprising 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 genus(es) 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. Thus, 9/15 embodied variants comprise a mutated residue in the CDR of the anti-CD3 antibody. 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, and that some of the amendable residues are located within antibody CDR regions; and further, that 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 which are 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, the 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 anti-CD27 antibody are quite different. 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, whereby 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 species of a genus of variant CD3 antibodies comprising a substituted cysteine residue conjugated to a fatty acid. The specifications do not provide any examples as to which residues may be mutated in any of the alternative genus(es) of “non-CD3” ICM antibodies 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 antibody directed against each ICM that is being claimed. This lack of definition complicates the determination of the boundaries of the claimed genus(es) 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 genus(es) 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 claim 8; 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. 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, claim 8 is rejected for lack of adequate written description support.
Response to Arguments
Applicant's arguments filed 4/14/2026 have been fully considered but they are not persuasive. Applicants contend that the invention is drawn to a “platform antibody” that is independent of the antigen to which the antibody binds (remarks, pg. 13, para. 2). That the platform antibody has a structure-function correlation in that all antibodies have a common structure, and that any antibody which has a fatty acid conjugated to it and performs the desired function of inhibiting binding of the antibody when the fatty acid is bound to albumin, but does not inhibit target binding when the fatty acid is not bound to albumin therefore meets the structure/function correlation of the platform antibody (pg. 13, para. 2 – pg. 14, para. 1); and that any antibody bound to a fatty acid that does not meet the desired functional limitations is not encompassed by the claims (pg. 12, para. 2). Applicants contend that the examiner is focused on the secondary structure of the antibody, in particular the sequences of the antibody which can be dependent on the target antigen; however, the secondary structure is not as critical as the tertiary structure. That it does not matter which antigen the antibody binds as long as the antibody has the desired functions after it is conjugated to a fatty acid (pg. 15, para. 1).
Conjugating a fatty acid to proteins to extend half-life of the proteins is well-known in the art, (see IDS references Lim et al., 2013 and Truessel et al., 2009). However, in doing so, the art teaches that it is important to consider the site of conjugation such that the fatty acid, when bound to albumin, does not interfere with the pharmacological action of the protein (i.e. binding its target epitope). The examiner understands that the instant invention involves fatty acids conjugated to antibodies wherein it is intended that, when the fatty acid is bound to albumin, the binding of the antibody to its target antigen is disrupted. Therefore, in low albumin environments, when the fatty acid is not bound to albumin, the antibody binds its intended target; thus imparting an in vivo site-specific property to the antibody. The invention requires 1) an antibody with an antigen-binding domain that is specific to its target antigen, and 2) a fatty acid conjugated to the antibody wherein, when the fatty acid is not bound to albumin, the antigen-binding domain maintains specificity to its target antigen. Thus, the site(s) of conjugation, for any antibody, will be carefully designed, precise residues, specific to the antibody, and identified through rigorous experimentation, such that the mutated residue for conjugating the fatty acid does not interfere with the inherent binding properties of the antibody to its target ligand; and the specifications should provide sufficient descriptive support that applicants possessed the claimed embodiments. That is, the examiner is directing the attention to the native antibody and mutating residues in the native antibody, not to the function of albumin-bound fatty acids conjugated to the antibody. The native antibody must be capable of binding it native target, even after residue mutations.
As described in the rejection above, an antibody binding domain comprises CDRs which impart the specificity and affinity to its target antigen, which are specific to any single antibody, and whereby even a single deleterious residue mutation can completely de-functionalize the antibody. Contrary to the applicant’s contention that the “platform antibody” does not need any particular target specificity, the examiner asserts that the claimed function, wherein the antibody maintains binding to its target antigen when the fatty acid is not bound to albumin, necessarily requires a functional (and specific) antigen binding domain; which is a required limitation of claim 1. Further, as known in the art, every distinct antibody has a structurally distinct antigen binding domain. The specifications disclose a single species of an anti-CD3 antibody, wherein the mutated residues that were reduced to practice occurred in the antigen binding domain; specifically, ~50% of the residue mutations occurred within the CDR domains. Some of the attempted residue substitutions de-functionalized the antibody, as described above. Thus, regarding a “platform antibody”, the examiner is referring to this “platform” as a genus, whereby the specifications describe, at most, a single platform using a specific anti-CD3 antibody species, whereby each variant of the binding domain, comprising a mutated residue conjugated to a fatty acid, is a variant species of the anti-CD3 antibody genus. Applicants must show descriptive support for possession of a representative number of examples of the hundreds of variant species within the genus of the single anti-CD3 antibody of the specifications; the specifications provide 19 such examples. Further, as an anti-CD27 antibody, or even alternative species of anti-CD3 antibodies, would have entirely different antigen-binding domains, each single antibody represents a separate genus (or platform) of antibodies encompassing all the potential variant species wherein a residue is mutated to conjugate a fatty acid, and wherein the variant species maintain the desired functionality. Thus, the applicants are not claiming a single “platform antibody”, the applicants are claiming thousands of specific antibody variants across hundreds of structurally distinct antibodies, each constituting a distinct genus (platform) from which the variants may be derived. Thus, the applicant’s contention that the examiner is (too) focused on secondary structure is incorrect; rather, the examiner is highlighting that the invention relies on the specific structure of the antigen binding domain of the antibody, whereby only precisely identified amino acid residues are amendable to conjugation with a fatty acid, such that the antibody maintains binding to its target when the fatty acid is not bound to albumin. The applicant’s contention that the invention is a platform, and does not require a specific antigen-biding domain is inconsistent with the art of antibody engineering, especially when the residues claimed as amendable for mutation occur in the CDRs. For example, consider an alternative scenario, wherein the specific mutations occur in an IgG CH1 domain, and whereby it is required that every variant antibody species comprises the mutated IgG CH1 domain. Then the claimed antibodies might not be dependent on the antigen-binding domain of the antibody. However, here the identified residues for mutation occur in the antigen-binding domain of the specific anti-CD3 antibody for which the experiments were directed. Thus, it is not true that, for example, a “K64C” substitution may occur in any other antibody, as most alternate antibodies will not have a K at position 64, and even in the chance that a random antibody has a K64 residue, there is no descriptive support that it would maintain binding to its target antigen after mutating the K64 residue. Thus, the instant invention requires the identification of the precise residues, of any claimed antibody, which are amendable for mutation and conjugation to a fatty acid, and whereby the antibody maintains binding to its target antigen. The specifications do not describe a universal “platform” whereby the substitution residues are consistent across any antibody species, regardless of specificity; the specifications teach specific residues of a specific anti-CD3 antibody species that function as the invention. The specifications do not demonstrate sufficient descriptive support for mutating residues across any anti-CD3 antibody, and provide zero guidance as it relates to mutating residues of any antibody which binds any of the ICMs of claim 7. There is no structure/function relationship to mutations in any other antibody beyond the single anti-CD3 antibody of the description, as every other antibody will comprise a distinct structure of the antigen-binding domain. Regarding the contention that the claims only encompass the mutated antibodies that actually work, the examiner re-iterates the arguments of the reply of 1/21/26, in that the applicants must show possession of the claimed invention, or a representative number of examples that encompass the full scope of the claimed invention. Here, the scope of claim 1 is enormously broad and the descriptive support for mutated resides in alternate antibodies is lacking. Applicant’s arguments are not found persuasive, and the rejections for lack of adequate written description support are maintained.
Claim Rejections - New
Claim Rejections - 35 USC § 103
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, 20 and 22 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 Bech et al., (ACS Medicinal Chemistry; 2018).
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 cholesterol, a sphingolipid (pg. 6, para. 0075) or glycolipid (pg. 53, claim 2).
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).
However, Pessi does not teach wherein the conjugated lipid binds albumin.
Bech teaches chemical strategies for half-life extension of biopharmaceuticals, including lipidation (title; pg. 577, col. 2). Bech teaches albumin contains 9 different fatty acid binding sites, and that molecules such as insulin and GLP-1 have been conjugated to lipids to improve their half-life via binding albumin (pg. 577, col. 2, para. 4). Bech teaches the various lipid chains, ceach comprising a fatty acid, that have been approved for insulin variants and GLP-1 analogs (pg. 578, Fig. 1).
It would have been obvious to one of skill in the art to select a sphingolipid or a glycolipid for conjugation to the antibody (i.e. Trastuzumab or Rituximab), as described by Pessi. One would have been motivated to do so given that lipidation of the antibody would extend its half-life via the binding of albumin to the fatty acid molecules of the conjugated lipids, as taught by Bech. There would have been a reasonable expectation for success given that Pessi teaches the specific residues of Trastuzumab or Rituximab that may be mutated to a cysteine, through which the lipid may be conjugated to the antibody without interfering with the antibody binding it natural ligand; and that sphingolipids or glycolipids are suitable lipids for conjugation, as described by Pessi. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
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 or glycolipid), 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 and glycolipids, comprise fatty acids; attaching glycolipids to a protein results in lipidation of the protein. Further, that fatty acids bind albumin as their primary mechanism of transport in the blood, and that lipidation of proteins extends the half-life of the proteins via binding albumin, as taught by Bech. Thus, as the combination of Pessi and Bech, resulting in lipidation of, for example, Rituximab for extending half-life, the combination makes obvious the structure of the antibody claim 1, wherein the antibody is conjugated to a fatty acid. Further, as the invention of Pessi and Bech makes obvious an antibody-fatty acid conjugate, whereby the fatty acid conjugated to the antibody or antigen binding fragment thereof is capable of binding albumin, the combination of Pessi and Bech make obvious 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 combination of Pessi and Bech makes obvious 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 combination of Pessi and Bech makes obvious instant claims 6.
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, the combination of Pessi and Bech makes obvious instant claim 20. Pessi teaches the linker may be PEG4, as described above (see pg. 16, para. 0141); thus Pessi makes obvious instant claim 22.
Claim Rejections - 35 USC § 103- New
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 Bech et al., (ACS Medicinal Chemistry; 2018) as applied to claims 1-3, 6, 20 and 22 above, and further in view of Dixit et al., (WO 2015/006749; published 1/15/2015).
The reasons why claims 1-3, 6, 20 and 22 are made obvious by the combination of Pessi and Bech 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; Bech teaches lipids comprises fatty acids which bind to albumin to extend the half-life of biopharmaceuticals. However, neither Pessi or Bech 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 is monovalent 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 extend the half-life of the antibody by binding albumin, as taught by Bech; 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 7-8, 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, Bech 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, Bech 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, Bech 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, Bech 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, Bech and Dixit make obvious instant claims 31-33 and 35.
Response to Arguments
Applicant's arguments filed 4/14/2026 have been fully considered but they are not persuasive. Applicants contend that Pessi is primarily drawn to derivatized cholesterol, and not fatty acids (remarks, pg. 16), and thus the exemplary embodiments of Pessi are not substantially identical to that of the instant claims, therefore anticipation cannot exist (pg. 20, para. 1). Applicants contend that as the structure of the lipids of Pessi and the fatty acids of the instant invention are not the same, thus there cannot be inherency of a result or characteristic (pg. 15, last paragraph). Along this line, applicants contend that fatty acids have a much higher affinity for albumin than cholesterol (pg. 18, paras. 2-3), while sphingolipids are larger and were not demonstrated by Pessi to allow the antibody to maintain target binding when they are conjugated to the antibody (pg. 19, paras. 1-2). Applicants contend that the function of the antibodies of Pessi differ from that of the instant invention (pg. 20, para. 2), thus an inherent property is only inherent if it is necessarily present in the prior art’s teaching (pg. 21, paras. 2-3).
The examiner has withdrawn the anticipation rejection of Pessi, instead the rejection is an obviousness rejection over Pessi and Bech. Pessi teaches that lipids can be conjugated to specific antibodies, at specific residues, whereby the lipids do not block the antibody from binding its primary target. Bech teaches that conjugating lipids to proteins increases the half-life of the protein via the fatty acid component of the lipid binding to albumin. Thus, while the motivation to combine Pessi and Bech may differ from that of the instant application, the result is an antibody conjugated to a lipid, comprising a fatty acid, whereby the fatty acid binds to albumin. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
While Pessi teaches attaching a cholesterol in a number of embodiments, Pessi also teaches, and claims, that sphingolipids or even glycolipids or gylcerophospholipids may be attached to the antibody. Thus, one of skill in the art, contemplating the half-life extension of, for example, OKT3 or Rituximab, according to the teachings of Bech, would look to Pessi for guidance as to which residues of OKT3 or Rituximab may be mutated to a cysteine residue to which a shingolipid may be attached, for the purpose of lipidation of the antibody to extend half-life. Thus, the combination of Pessi and Bech, for the purpose of extending half-life, would not rely on cholesterol being conjugated; rather they teach that lipids comprising fatty acids (e.g., glycolipids or sphingolipids) may be attached to distinct antibodies at specific locations. As discussed in the 112(a) rejection for descriptive support, Pessi teaches the specific amino acid residues of specific antibody species that may be mutated to a cysteine, for attachment of a lipid molecule, wherein the antibody maintains binding to its epitope. Thus, while the goal of the constructs of Pessi are to improve binding by adding a plasma membrane binding moiety, the combination constructs of Pessi and Bech, comprising a lipid comprising a fatty acid which binds to albumin, are to increase antibody half-life. As the constructs of the combination of Pessi and Bech comprise a fatty acid, which binds to albumin, wherein the lipid is conjugated at the same sites of conjugation of the instant embodiments, the combination constructs of Pessi and Bech would inherently have decreased binding to the target antigen when the fatty acid is bound to albumin, and maintain binding to the target antigen when the lipid fatty acids are not bound to albumin. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The applicants contend that a sphingolipid conjugated to the antibody would disrupt the antibody binding its target antigen. However, Pessi teaches attaching lipid structures to the antibodies, whereby the lipids do not interfere with antibodies binding their target antigen. Specifically, Pessi teaches “It was shown that antibodies capable of specifically binding their respective epitope could be modified to additionally bind the plasma membrane of a target cell; and that surprisingly such modifications are capable of increasing the potency of the antibodies,” (Pessi; pg. 1, para. 0008). Thus, Pessi teaches lipids may be conjugated to antibodies whereby the antibodies maintain binding their epitope, whereby the residues for conjugation are the same as those disclosed for the antibodies of Pessi, and whereby the lipids comprise fatty acid(s). It is inherent to the construct of the combination of Pessi and Bech that, when the fatty acid is bound to albumin, binding the epitope is diminished. This is because the reason for conjugating a lipid to the antibody is to bind albumin to increase half-life, as taught by Bech, and the position of the lipid conjugation occurs in the same antibodies, at the same residues of the instant invention, as taught by Pessi. The disruption of target binding when the fatty acid is bound to albumin is inherent due to the size and location of the albumin, and naturally flows from a fatty acid binding albumin. Thus, the constructs of Pessi and Bech are substantially similar in structure to those of the instant claims, and therefore inherently possess the same properties. If applicants believe the fatty acids of the instant embodiments provide an unexpected advantage over antibodies conjugated to a lipid comprising fatty acids, with the same sites of conjugation, then applicants may present comparison data demonstrating the technological advantage of conjugating fatty acids over lipids in the invention. In view of the obviousness rationale of the current rejections, applicant’s arguments are not found persuasive.
Double Patenting-New
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.
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Claims 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 Bech et al., (ACS Medicinal Chemistry; 2018) 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, Bech and Dixit is described above. Specifically, the combination bispecific antibody of Pessi, Bech 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, Pessi and Bech, 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, as taught by Pessi, would extend the half-life of the antibody and improve its therapeutic applications, as taught by Bech; 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, Bech and Dixit, make obvious the bispecific antibody of instant claims 11-12 and 17. Claims 10-11 and 13 of app ‘029 in view of Pessi, Bech 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, Bech 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 4/14/2026 have been fully considered but they are not persuasive. Applicants contend that the construct of claim 1 is a monoclonal antibody and not a bispecific antibody, thus app ‘029 fails to disclose or suggest each and every element of claim 1 (remarks, pg. 22, para. 4). Applicants contend that Pessi fails to anticipate the structure of claim 1 as discussed previously, and Dixit fails to make up for the deficiencies.
The current rejections are based on the obviousness of combining Pessi and Bech, as discussed above, and therefore make obvious the invention of claim 1. Thus, the combination of app ‘029, Pessi, Bech and Dixit make obvious an antibody conjugated to a fatty acid, via conjugation to a lipid, for the purposes of extending the half-life of the antibody; app ‘029 and Dixit teach the structures of the instant claims wherein the antibody is bispecific and wherein the H1L1 comprise a charge pair as described in instant claim 17. The examiner has removed claim 1 from the rejection, other than as providing the basis for the bispecific antibodies of claim 11. The combination of Pessi, Bech and Dixit make obvious the monoclonal antibody of instant claim 1, as discussed above, app ‘029 and Dixit make obvious a bispecific antibody thereof. As the examiner maintains that the combination of Pessi and Bech make obvious the construct of instant claim 1, applicant’s arguments against the Pessi reference are not persuasive.
Allowable Subject Matter
Claims 18-19 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. Specifically, SEQ ID NOs: 15, 20, 29 and 31, each comprising one or two specific amino acid residue substitutions for conjugating a fatty acid over the known base sequences, are free of the prior art, when each sequence requires 100% amino acid sequence identity.
Conclusion
No claims are allowed. Claims 1-17, 20, 22, 27-33 and 35-38 are rejected; claims 18-19 are objected to.
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
Prosecution Insights