Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Species A1 (a single and specific CD38 binding arm comprising HCDR1-3 of SEQ ID NOs: 42, 44, and 46; LCDR1-3 of SEQ ID NOs: 50, 52, and 54; HCVR of SEQ ID NO: 40; LCVR of SEQ ID NO: 48; heavy chain of SEQ ID NO: 58; and light chain of SEQ ID NO: 60) and Species A2 (a single and specific 4-1BB binding arm comprising a first (R1) and second (R2) binding region according to HCDR1-3 of SEQ ID NOs: 64, 66, 68; LCDR1-3 of 50, 52, and 54; HCVR of SEQ ID NO: 63; LCVR of SEQ ID NO: 48; heavy chain of SEQ ID NO: 84; and light chain of SEQ ID NO: 60) in the reply filed on October 23, 2025 is acknowledged.
Claims 30-31 and 38-41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on October 23, 2025.
Note well, SEQ ID NO: 66 is “000” in the sequence listing and has been search as the LCDR2 according to IMGT number system, “AAS”.
Status of Claims
Claims 1-5, 8-55, 57, 59-60, and 77 are currently pending. Claims 1-5, 8-29, 32-37, 42-55, 57, 59-60, and 77 are under examination and claims 30-31 and 38-41 are withdrawn as set forth above.
Claim Objections
37 CFR 1.71(a) requires the claims to be written in “full, clear, concise, and exact terms.” Claims 9, 16, 43, 49-51, 55, 57, 59 and 60 are objected to because of the following informalities:
Claim 9 in line 4 has a comma after 4-6-8, which is grammatically informal.
Claim 16 is missing “of” between “molecule” and “claim 1” in line 1.
In claims 49-51, “encoding for” is a grammatical informality and may be “coding for” or “encoding”.
Claims 43, 55, 57, 59, and 60 each recite in one more line “antigen” and “binding” without a hyphen between the terms, which is inconsistent with the formatting used in the majority of the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 8-11, 13-28, 33-37, 43-44, 48-55, 57, and 59-60 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.
Claims 1, 13, 14, 20, 21, 27, and 43 claim antigen binding components based on three CDRs of a specifically recited HCVR or LCVR sequences. At the time of instant filing there were a number of numbering schemes that were used to specifically define the location of CDRs. However, the skilled artisan would have been aware numbering schemes are not immutable and are iteratively improved upon for different purposes. For the purpose of, e.g., humanization numbering schemes are required to define the boundaries of CDRs for the purpose of determining where to modify the sequence without interrupting antigen binding capacity. Notably, not all antigen-binding residues will be found in the CDRs as defined by a particular scheme. The metes and bounds of an antigen-binding region claimed by the CDRs of a given HCVR and/or LCVR would be indefinite because different interpretations of the boundaries of a CDR may arise. For example, would a claim to an antigen binding region comprising a series of three or more subsequences containing residues that contribute to epitope binding but are outside of the well-known number schemes infringe on an antigen binding region claimed as comprising the CDRs of a given HCVR or LCVR sequence?
For the purpose of applying prior art, a teaching on any antigen binding domain comprising CDRs defined by a number scheme known at the time of instant filing is interpreted as reading on the claims.
Claims 2-5, 8-11, 15-19, 22-26, 33-37, 48-55, 57, and 59-60 are rejected by virtue of their dependency.
Claim 28 recites an antigen binding regions comprising HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3. The format of using hyphens is commonly used in the art to indicate links between domains of a polypeptides with the left-most domain representing the N-terminus and the right-most domain representing the C-terminus. In the instant case, the format results in multiple interpretations such that the metes and bounds of the instants claim 28 are not clear. Some skilled artisans would interpret the format as limiting the claims to an antigen binding domain comprising a single polypeptide, e.g., an scFv wherein the HCVR is N-terminal of the LCVR. Other skilled artisan would argue that instant claim 28 is not limited to the aforementioned interpretation and include embodiments in which the HCVR and LCVR are on separate polypeptides, e.g. Fab. Therefore, it would be unclear whether an Fab comprising each CDR infringes on the claimed subject matter.
To advance prosecution on the merits, the scope of claim 28 is interpreted as not requiring the CDRs of the HCVR and LCVR are on the same polypeptide (e.g. art teaching the limitation of an Fab comprising the CDRs reads on the claimed subject matter).
Regarding claim 35, the of parentheses in “(EU numbering)” renders the claim indefinite because it is unclear whether the limitation(s) inside the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
Claim 35 is interpreted as “…Y436 according to EU numbering.”
Claims 33 and 44 are directed to the antigen-binding molecule of claims 1 and 43, respectively, wherein the molecule is an antibody. The metes and bounds of claim 44 are indefinite because different skilled artisans would arrive at different interpretations of the structure claimed. A naturally occurring antibody comprising HCVRs and LCVRs is a tetrameric molecule has a Y shape with two dimerized heavy chains which are paired with respective light chains. Said antibody comprises two Fab regions composed of VH-CH1 and VL-CL and an Fc region comprising at least dimerized hinge-CH2-CH3 regions. Each binding region formed by the pairing of a HCVR and LCVR comprises 6 CDR. The antigen binding molecule of claim 43, at a minimum, two “binding arms”, wherein one comprises at least three CDRS of an HCVR and three CDRs of a LCVR and the other binding arm comprises two antigen binding domains each comprising three CDRS of an HCVR and three CDRs of a LCVR. Thus, the “antibody” of claim 44 necessarily deviates from a natural structure. Some skilled artisan would argue that the “antibody” of claim 44 requires the naturally occurring Y shape wherein each branch of the Y is one of the two antigen binding arm and the structure further comprises an Fc region. Other skilled artisans would argue that the term “antibody” should be interpreted more broadly to encompass any arrangement of the two antigen binding arms of the antigen-binding molecule of claim 43, which would fail to further limit the scope of the invention described in claim 43. In conclusion, the structural limitations of claim 44 are unclear and a skilled practitioner would not be able to determine when infringement upon the claim occurs.
To advance prosecution on the merits, a teaching of the prior art that satisfies all limitations of the molecule of claim 43 is interpreted as reading on claim 44.
Claim 51 recites “encoding for LCVR”, however claim 1 recites a LCVR of a first antigen-binding arm, a LCVR of a first antigen-binding region on a second antigen binding arm, and a LCVR of a second antigen-binding region on a second antigen-binding arm. The metes and bounds of claim 51 are indefinite because it is unclear to which LCVR of claim 1 that claim 51 refers.
For the purpose of applying prior art, a nucleic acid encoding any one the three LCVRs of claim 1 is interpreted as reading on claim 51.
Claim 52 recites the limitation "the isolated nucleic acid molecule of claim 1" in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite an isolate nucleic acid molecule.
For the purpose of applying art, claim 52 is interpreted with the scope of “an expression vector containing a nucleic acid molecule encoding the bispecific-antigen binding molecule of claim 1.”
Claims 53-55 are rejected by virtue of its dependency on claim 52.
Claim 55 sets forth growing host cell of claim 53 wherein the host cell comprises a nucleic acid sequence encoding a HCVR of “a multispecific antigen binding molecule antigen binding arm A1”, a second nucleic acid encoding a HCVRs of “a multispecific antigen binding molecule antigen binding arm A2”, and a common LCVR. Since the scope of the host cell of claim 53 has been interpreted as comprising a vector comprising a nucleic acid sequence encoding the bispecific-antigen binding molecule of claim 1, the metes and bounds of the nucleic acid sequences is unclear. Some skilled artisans would argue that each nucleic acid molecule recited in claim 55 refers back to a HCVR of claim 1, wherein the scope of the antigen-binding molecule of claim 1 is further limited to comprising a common LCVR. Other skilled artisans would argue that each nucleic acid molecule recited in claim 55 encompasses the scope of an additional HCVR/LCVR to the HCVRs and LCVRs recited in claim 1 because claim 55 uses the language of “a” HCVR and not “the” HCVR. Moreover, some skilled artisans would argue that the annotations “A1” and “A2” which are not used in claim 1 further support the position that the nucleic acids recited in claim 55 are directed to different HCVRs/LCVRs that the HCVRs/LCVRs recited in claim 1.
Claims 15, 22, and 28 recite “SEQ ID NO: 66” which is empty in the sequence listing. Thus, the metes and bound of the antigen binding molecule comprising SEQ ID NO: 66 is indefinite because a person of ordinary skill would not be able to determine when a sequence infringes upon the claimed subject matter.
For the purpose of advancing prosecution, SEQ ID NO: 66 has been searched and examined as “AAS.”
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 13-18 and 20-25 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.
As was well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level. By the time the invention was made, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33 (IDS) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1).
Claims 13-18 and 20-25 describe a genus of antibodies that bind to 4-1BB that are structurally claimed by less than the full set of 6 CDRs (e.g. three CDRs of the LCVR or HCVR, or just an LCVR, or just an HCVR). Therefore, claims 13-18 and 20-25 encompasses a large amount of variation within the genus of antigen binding proteins that specifically bind to 4-1BB because the pairing CDRs and or LCVR or HCVR may have any sequence of amino acids.
The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., binding to 4-1BB), claiming antibodies with specific properties, e.g., binding to 4-1BB, can result in a claim that does not meet the written description requirement even when the polypeptide sequence of 4-1BB bound by the antibody is known, because antibodies with those properties have not been adequately described. See Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
MPEP § 2163 states:
"The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice ... reduction to drawings ... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. In unpredictable arts a widely variant genus cannot be represented by only one species. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Furthermore, establishment of a ‘reasonable structure-function correlation’ can also describe a genus and may be established ‘by the inventor as described in the specification,’ or ‘known in the art at the time of the filling date.’ See MPEP 2163 (II)(A)(3)(a)(ii) and Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that ‘only describe[d] one type of structurally similar antibodies’ that ‘are not representative of the full variety or scope of the genus.’)."
Applicant discloses 6 anti-4-1BB clones (see pg. 59 in Table 3) and no additional species within the scope of the claimed anti-4-1BB antibodies were found in the prior art. However, 6 antibodies is a very small fraction of the antibodies described in claims 13-18 and 20-25 and is not representative of the full scope of the variation present in this claimed genus. Thus, one of ordinary skill in the art would not be able to reasonably say that the Applicant possessed a representative number of species that reflects the variation of the claimed genus.
The factual inquiry now turns upon whether there is a correlation between structural and functional characteristics. To meet this requirement in the instant case, the specification must describe structural features that convey the claimed binding activity, a prerequisite for utility in the recited methods of treating. As noted above, the art generally accepted that the combination of the CDRs/HVRs within the VH and VL pair of an antibody were essential for binding specificity. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for antibodies other than those comprising either all six CDRs/HVRs (in the context of VH and VL regions) of one parental antibody, or the VH and VL of one parental antibody.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011). Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.)
The art is highly unpredictable in respect to correlations between the structure and binding properties of CDRs.
Rudikoff et al. found that a single amino acid change in a CDR completely altered antigen-binding specificity (Rudikoff et al. Proc Natl Acad Sci 1982. 79: 1979-1983; cited herewith, pg. 1982, left column, second full paragraph). Bedouelle et al. (FEES J. 2006 Jan;273(1):34-46; cited herewith) examined the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a > 100 fold drop in the “off rate” for ligand dissociation (Bedouelle et al., pg. 38-39; see Table 2). Bedouelle suggests that some mutations had a direct effect on antigen binding while others indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section). This illustrates the unpredictability of making mutations within the CDRs of an antibody, especially the CDR3 domains. Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28; cited herewith) teaches that antigen binding is resultant from the 6 CDRs, or hypervariable regions, the variable region of an antibody (see, page 416, column bridging paragraph, emphasis added). Vajdos used a shotgun scanning mutagenesis using phage displayed libraries of protein mutants, which required extensive experimentation to comprehensively scan the potential CDR sequence space (see page 416, right column, 2nd paragraph and pages 425-427, Materials and Methods). Furthermore, even after performing this comprehensive scanning mutagenesis of all CDR residues from the particular anti-ErB2 antibody, Vajdos would still not have been able to say which CDR residues were actually involved in antigen binding, and which were involved in stabilizing the secondary and tertiary structure of the CDRs within the context of the heavy and light chains as a whole, without the structure of the unbound antigen-binding site of the antibody to aid in their analysis (see, in particular, Discussion, pages 422- 425). Rather, Vajdos needed to perform not only a comprehensive shotgun scanning mutagenesis of all CDR residues of the antibody under study, but also needed a structure of the unbound antigen binding site in hand to gain a sufficient understanding of the contribution of each CDR to antigen-binding to adequately predict which CDR residues can be changed, and to what extent, or in what context of additional compensatory mutations in other regions of the antibody.
Collectively, Rudikoff et al. Bedouelle et al., and Vajdos et al. demonstrate the amino acids of a CDR that are responsible for binding with a particular antigen cannot be determined by observation of the amino acid sequence alone. Indeed, Vajdos et al. showed it required the epitope of the antigen as well. Additionally, the ability to bind to a particular antigen is extremely sensitive to changes in CDR sequences.
In conclusion, there are no representative species in the art and the species disclosed in the specification are not sufficient to represent the full breadth of the claimed invention according to instant claims 13-18 and 20-25. Furthermore, a structure-function correlation is not shown in the specification or the art to account for the high degree of variability of the CDRs as laid forth in the instant claims. Claims 13-18 and 20-25 are rejected under of 35 U.S.C. 112(a) for failing to comply with the written description requirement.
Claim Rejections - 35 USC § 102
Claims 49 and 51 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by DiLillo et al. in US 2022/0089766 A1 published March 24, 2022 and effectively filed on Sept. 18, 2020.
The applied reference has a common inventors (David DiLillo, Aynur Hermann, Kara Olson, and Erica Ullman) and assignee (Regeneron Pharmaceuticals, Inc.) with the instant application. Based upon the earlier publication and effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1) and 102(a)(2).
DiLillo teaches nucleic acid molecules encoding the HCVR according to SEQ ID NO: 2 (amino acid) encoded by SEQ ID NO: 1 (nucleic acid) and the LCVR according to SEQ ID NO: 18 (amino acid) encoded by SEQ ID NO: 19 (nucleic acid) (pg. 30 in Table 1 and pg. 31 in Table 2). DiLillo’s nucleic acid molecules anticipates the isolated nucleic acid molecules of instant claim 49 and 51 as demonstrated by alignment of the amino acid sequences below.
PNG
media_image1.png
228
723
media_image1.png
Greyscale
PNG
media_image2.png
184
724
media_image2.png
Greyscale
This rejection under 35 U.S.C. 102(a)(1) and 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A) and 102(b)(1)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) and 102(b)(1)(B) if the same invention is not being claimed; or (3) a combination of the 102(b)(1)(A) or 102(b)(1)(B) exceptions with a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
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 1-5, 8-12, 33-36, 48-55, 57, and 59-60 are rejected under 35 U.S.C. 103 as being obvious over DiLillo et al. in US 2022/0089766 A1 published March 24, 2022 and effectively filed on Sept. 18, 2020 in view of Koller in WO 2018/127473 A1 published on July 12, 2018.
The applied reference has a common inventors (David DiLillo, Aynur Hermann, Kara Olson, and Erica Ullman) and assignee (Regeneron Pharmaceuticals, Inc.) with the instant application. Based upon the earlier publication and effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1) and 102(a)(2).
DiLillo teaches an anti-CD38 antigen binding protein comprising the heavy chain sequence according to SEQ ID NO: 26 and the light chain according to SEQ ID NO: 30 (see embodiment (5) on pg. 9 in the second col.), which teach the limitations of the anti-CD38 antigen binding domain recited in instant claims 1, 8-12, and 36.
PNG
media_image3.png
540
828
media_image3.png
Greyscale
PNG
media_image4.png
302
826
media_image4.png
Greyscale
Regarding instant claim 3, DiLillo on pg. 14 in ¶ [0130] teaches that multispecific antibodies may bind to a different epitope on the same antigen. Relating to instant claim 34, the heavy chain sequence of DiLillo SEQ ID NO: 26 as shown above is an IgG1 isotype sequence (see also ¶ [0178] on pg. 19 spanning pg. 20). DiLillo teaches H435R and Y436 mutations on CH3 according to EU numbering (see ¶ [0183] spanning the first and second col. on pg. 20, relating to instant claim 35. On pg. 25 in ¶ [0220], DiLillo teaches that the antigen binding molecules are formulated in pharmaceutical compositions comprising suitable carriers, relating to instant claim 48. Relating to instant claims 52-53, DiLillo in ¶ [0043] on pg. 4 teaches expression vectors and host cells. Relating to instant claims 54 and 55, DiLillo teaches methods of expressing bispecific antigen binding molecules by culturing CHO cells comprising nucleic acid sequences encoding light / heavy chains (see ¶ [0252] on pg. 29). Relating to instant claim 57 and 59-60, DiLillo teaches a method of inhibiting the growth of a plasma cells (see, e.g., claim 51) and that the CD38 binding arm is useful for binding to tumors expressing CD38, e.g. plasma cells (¶ [0086] on pg. 7). The anti-CD38 of DiLillo is generally directed to bispecific constructs that also bind CD28, wherein the intended purpose of the CD28 binding arm is to provide co-stimulation of T cells. Id.
While DiLillo teaches bispecific antigen binding proteins comprising a CD38 antigen binding arm relating to the instantly claim sequences and a domain that provides co-stimulation of T cells, DiLillo does not teach the anti-CD38 binding arm in an antigen binding protein that comprises an antigen binding arm having two binding sites for 4-1BB.
However, Koller teaches bispecific antibodies comprising at least on antigen binding domain capable of binding to 4-1BB and at least one antigen binding domain capable of specific binding to a target cell antigen (see pg. 3 in lines 12-25), relating to instant claim 33. Fig. 1D and 1E shows a bispecific format having two anti-4-1BB Fab fragments and a C-terminally fused (cross-fab) that binds a target cell (see pg. 15 in lines 25-28), relating to the instant claims as the N-terminal arm comprises two anti-4-1BB binding domains and the C-terminal arm comprises a binding site specific for a target cell. Fig. 5A also shows a bispecific antibody embodiment that comprises two anti-4-1BB on the same portion of the N-terminal arm. 4-1BB (CD137) induces IFNγ and proliferation of NK cells, promotes DC activation, but is best known as a co-stimulatory receptor on T cells that stimulates lymphokine secretion, enhances proliferation, and reduces sensitivity to activation induced cell death. (see pg. 1 line 23 through pg. 2 in line 13). 4-1BB stimulation on T cell is particularly relevant promoting to anti-tumor immunity. Id. Regarding instant claim 2, Figs 3 and 6 show results from a bispecific antibody bivalent for 4-1BB clone 20H4.9. Koller teaches a bispecific antigen binding molecule comprising four anti-4-1BB antigen binding domains comprising two heavy chains comprising VHCH1-peptide linker-VHCH1, relating to instant claim 4. Regarding instant claim 5, see peptide linkers on pg. 98, particularly SEQ ID NOs: 110, 114, and 115. Regarding instant claim 50, Koller on pg. 13 in lines 4-5 teaches a polynucleotide encoding the bispecific antibody.
It would have been prima facie obvious to a person of ordinary skill in the art to substitute the anti-CD28 binding arm of DiLillo’s anti-CD38 x anti-CD28 bispecific antibody with an anti-4-1BB binding arm comprising two binding sites as taught by Koller. The skilled artisan would have expected that the substitution of an anti-41BB binding arm for the anti-CD28 would result in the intended purpose of co-stimulation of T cells disclosed by DiLillo because Koller teaches that the anti-4-1BB also stimulates T cells. Alternatively, where Koller teaches that the bispecific anti-4-1BB construct also binds to a target cell antigen, one of skill would have found it obvious to use the anti-CD38 binding site from DiLillo’s bispecific construct as the binding site targeting a cell antigen. Similarly, the skilled artisan would have been motivated because both DiLillo and Koller teach the same intended purpose. In other words, the skilled artisan would have been able to “fit the teachings of [DiLillo and Koller] together like pieces of a puzzle." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007) at 420, 82 USPQ2d 1397.” Therefore, in view of the level of ordinary skill and design incentives to create bispecific antibodies that activate T cells and target T cells to a CD38+ tumor, the skilled artisan would have had the motivation to combine DiLillo’s anti-CD38 T-cell activating bispecific antibody with an anti-4-1BB binding arm comprising two binding sites as taught by Koller, and the ordinarily skilled person would have arrived at the instantly claimed invention with a reasonable expectation of success in doing so.
This rejection under 35 U.S.C. 102(a)(1) and 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A) and 102(b)(1)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) and 102(b)(1)(B) if the same invention is not being claimed; or (3) a combination of the 102(b)(1)(A) or 102(b)(1)(B) exceptions with a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
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 1-2, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 11,905,332 in view of Koller in WO 2018/127473 A1 published on July 12, 2018.
‘332 teaches an anti-CD38 antigen binding protein comprising the heavy chain sequence according to SEQ ID NO: 26 and the light chain according to SEQ ID NO: 30 (see embodiment (5) on pg. 9 in the second col.), which teach the limitations of the anti-CD38 antigen binding domain recited in instant claims 1, 8-12, and 36.
PNG
media_image3.png
540
828
media_image3.png
Greyscale
PNG
media_image4.png
302
826
media_image4.png
Greyscale
Relating to instant claim 34, the heavy chain sequence of ‘332 SEQ ID NO: 26 as shown above is an IgG1 isotype sequence. In claim 24 ‘332 teaches a pharmaceutical compositions further comprising a, relating to instant claim 48. Relating to instant claim 57 and 59-60, ‘332 teaches that the bispecific antibody demonstrates decreased tumor burden in subjects with multiple myeloma, to have demonstrated this property the bispecific antibody would necessarily have had to be administered to the subject. The anti-CD38 of DiLillo is generally directed to bispecific constructs that also bind CD28, wherein the intended purpose of the CD28 binding arm is to provide activation of T cells. See claim 27(a).
While ‘332 teaches bispecific antigen binding proteins comprising a CD38 antigen binding arm relating to the instantly claim sequences and a domain that provides activation of T cells, ‘332 does not teach the anti-CD38 binding arm in an antigen binding protein that comprises an antigen binding arm having two binding sites for 4-1BB.
However, Koller teaches bispecific antibodies comprising at least on antigen binding domain capable of binding to 4-1BB and at least one antigen binding domain capable of specific binding to a target cell antigen (see pg. 3 in lines 12-25), relating to instant claim 33. Fig. 1D and 1E shows a bispecific format having two anti-4-1BB Fab fragments and a C-terminally fused (cross-fab) that binds a target cell (see pg. 15 in lines 25-28), relating to the instant claims as the N-terminal arm comprises two anti-4-1BB binding domains and the C-terminal arm comprises a binding site specific for a target cell. Fig. 5A also shows a bispecific antibody embodiment that comprises two anti-4-1BB on the same portion of the N-terminal arm. 4-1BB (CD137) induces IFNγ and proliferation of NK cells, promotes DC activation, but is best known as a co-stimulatory receptor on T cells that stimulates lymphokine secretion, enhances proliferation, and reduces sensitivity to activation induced cell death. (see pg. 1 line 23 through pg. 2 in line 13). 4-1BB stimulation on T cell is particularly relevant promoting to anti-tumor immunity. Id. Regarding instant claim 2, Figs 3 and 6 show results from a bispecific antibody bivalent for 4-1BB clone 20H4.9. Koller teaches a bispecific antigen binding molecule comprising four anti-4-1BB antigen binding domains comprising two heavy chains comprising VHCH1-peptide linker-VHCH1, relating to instant claim 4. Regarding instant claim 5, see peptide linkers on pg. 98, particularly SEQ ID NOs: 110, 114, and 115. Regarding instant claims 49-52, Koller on pg. 13 in lines 4-5 teaches a polynucleotide encoding the bispecific antibody. The polynucleotide is maintained in host cells including CHO cells, relating to instant claims 53-54 (see pg. 44 in lines 20-22 and pg. 46 in lines 2-6). Relating to instant claim 55, Koller teaches a method of producing a bispecific antigen binding molecule on pg. 80 in lines 18-24.
It would have been prima facie obvious to a person of ordinary skill in the art to substitute the anti-CD28 binding arm of ‘332’s anti-CD38 x anti-CD28 bispecific antibody with an anti-4-1BB binding arm comprising two binding sites as taught by Koller. The skilled artisan would have expected that the substitution of an anti-41BB binding arm for the anti-CD28 would result in the intended purpose of activation of T cells disclosed by ‘332 because Koller teaches that the anti-4-1BB also stimulates T cells. Alternatively, where Koller teaches that the bispecific anti-4-1BB construct also binds to a target cell antigen, one of skill would have found it obvious to use the anti-CD38 binding site from ‘332’s bispecific construct as the binding site targeting a cell antigen. Similarly, the skilled artisan would have been motivated because both ‘332 and Koller teach the same intended purpose. In other words, the skilled artisan would have been able to “fit the teachings of [DiLillo and Koller] together like pieces of a puzzle." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007) at 420, 82 USPQ2d 1397.” Therefore, in view of the level of ordinary skill and design incentives to create bispecific antibodies that activate T cells and target T cells to a CD38+ tumor, the skilled artisan would have had the motivation to combine ‘332’s teachings anti-CD38 T-cell activating bispecific antibody with an anti-4-1BB binding arm comprising two binding sites as taught by Koller, and the ordinarily skilled person would have arrived at the instantly claimed invention with a reasonable expectation of success in doing so.
Claims 1-2, 3, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 11,905,332 in view of Koller in WO 2018/127473 A1 published on July 12, 2018; as applied to claims 1-2, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 above and further in view of Keyt in WO 2018017761 A1 published January 25, 2018.
See ‘332 in view of Koller as applied to claims 1-2, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 above.
While ‘332 in view of Koller teaches a bispecific antibody comprising an anti-CD38 binding arm and an anti-4-1BB antigen binding arm with two binding site, ‘332 in view of Koller does not teach that the anti-4-1BB binding sites bind to different epitopes on 4-1BB.
The prior art contained a "base" device (method, or product) upon which the claimed invention can be seen as an "improvement."
Koller teaches that the tetravalent embodiment of the 4-1BB binding arm comprising multiple anti-4-1BB had decreased mean fluorescent intensity (MFI) due to internal competition for 4-1BB-specific epitopes (pg. 136 in lines 22-23). The tetravalent construct of Koller used the same antigen-binding domain, 20H4.9, which binds the same epitope, which Koller teaches is the reason that the tetravalent construct had less favorable properties. Thus, Koller teaches a base device upon which the claimed invention described in claim 3 is an improvement upon because it solves the problem of Koller by binding to different epitopes on 4-1BB.
The prior art contained a "comparable" device (method, or product that is not the same as the base device) that has been improved in the same way as the claimed invention.
Keyt teaches multimeric agonistic anti-4-1BB binding molecules comprising multiple anti-4-1BB binding domains that bind to bind to two or more different 4-1BB epitopes (see pg. 3 in ¶ [0011]; see also claim 11).
One of ordinary skill in the art could have applied the known "improvement" technique in the same way to the "base" device (method, or product) and the results would have been predictable to one of ordinary skill in the art.
It was within the level of skill in the art at the time of instant filing to use anti-4-1BB binding sites that bind different epitopes of anti-4-1BB in the construction of a bispecific antibody of ‘332 in view of Koller. Given the ordinary level of skill and the evidence of record, the skilled artisan would have had a reasonable expectation of success at arriving at the bispecific antigen binding molecule of claim 3.
"It's enough … to show that there was a known problem … in the art, that [another reference] … helped address that issue, and that combining the teachings of [the two references] wasn't beyond the skill of an ordinary artisan. Nothing more is required to show a motivation to combine under KSR." See Intel Corp. v. PACT XPP Schweiz AG, 61 F.4th 1373, 1380-81, 2023 USPQ2d 297 (Fed. Cir. 2023) In conclusion, it would have been prima facie obvious to a person of ordinary skill in the art to modify the bispecific antibody of ‘332 in view of Koller to have multiple 4-1BB binding sites that bind different epitopes of 4-1BB as suggested by Keyt.
Claims 1-2, 4-5, 8-12, 33-34, 35, 36, 48-55, 57, and 59-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 11,905,332 in view of Koller in WO 2018/127473 A1 published on July 12, 2018; as applied to claims 1-2, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 above and further in view of Brinkmann et al. mAbs. 2017. 9(2):182-212.
See ‘332 in view of Koller as applied to claims 1-2, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 above.
While ‘332 in view of Koller teaches a bispecific antibody comprising an anti-CD38 binding arm and an anti-4-1BB antigen binding arm with two binding site, ‘332 in view of Koller does not teach the mutations H435R and Y436F.
However, Brinkmann teaches that purification of bispecific antibodies can be improved by introducing H435A and Y436F mutations into one of the two heavy chains of a bispecific antibody (see pg. 192 in the first ¶ of the second col.). The mutations ablate the ability of protein A to bind to the heavy chain. Therefore, dimers of two heavy chain having the mutation, which do not form a bispecific antibody, cannot be purified by protein A chromatography, but dimers of one heavy chain having the mutations with one not having the mutations can be purified and are bispecific.
It would have been prima facie obvious to the skilled artisan to construct the bispecific anti-CD38 x anti-41BB antibody of ‘332 in view of Koller using the method for enhancing purification by introducing H435A and Y436F mutations into one of the two heavy chains. The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). Brinkmann explicitly teaches that there was an advantage to the aforementioned mutational strategy, therefore the skilled artisan would have been motivated to make the modification of introducing H435A and Y436F mutations into a heavy chain of ‘332 in view of Koller’s anti-CD38 x anti-41BB antibody. Given that each antibody has a limited number of heavy chains (two), it would have been prima facie obvious to try the second heavy chain, i.e. a heavy chain having the 4-1BB targeting arm. In view of the level of ordinary skill in the art and explicit teachings, the skilled artisan would have a reasonable expectation of success. Therefore, it would have been obvious to a person of ordinary skill to construct the bispecific anti-CD38 x anti-41BB antibody of ‘332 in view of Koller using the method for enhancing purification by introducing H435A and Y436F mutations into a heavy chain comprising the anti-4-1BB binding sites.
Claims 1-2, 4-5, 8-12, 33-34, 36, 48-55, and 57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71-96, 98-102, and 104-107 of copending Application No. 18/420,588 in view of Koller in WO 2018/127473 A1 published on July 12, 2018 and Xu in WO 2018/107069 A1 published June 14, 2018.
‘588 claims 75 and 84 teach a nucleotide encoding an anti-CD38 binding domain as shown below, relating to instant claims 1, 8-12, 36, and 49-51:
PNG
media_image5.png
540
828
media_image5.png
Greyscale
[AltContent: rect]
PNG
media_image6.png
356
975
media_image6.png
Greyscale
Relating to instant claim 34, the heavy chain sequence of ‘332 SEQ ID NO: 26 as shown above is an IgG1 isotype sequence. Claims 93-94 of ‘588 teaches an expression vector and host cell, relating to instant claims 52-53. Claim 95 of ‘588 teaches a method of producing an anti-CD38 antibody, relating to instant claim 55.
While ‘588 teaches bispecific an anti-CD38 binding site, ‘332 does not teach the anti-CD38 binding arm in an antigen binding protein that comprises an antigen binding arm having two binding sites for 4-1BB.
However, Koller teaches bispecific antibodies comprising at least on antigen binding domain capable of binding to 4-1BB and at least one antigen binding domain capable of specific binding to a target cell antigen (see pg. 3 in lines 12-25), relating to instant claim 33. Fig. 1D and 1E shows a bispecific format having two anti-4-1BB Fab fragments and a C-terminally fused (cross-fab) that binds a target cell (see pg. 15 in lines 25-28), relating to the instant claims as the N-terminal arm comprises two anti-4-1BB binding domains and the C-terminal arm comprises a binding site specific for a target cell. Fig. 5A also shows a bispecific antibody embodiment that comprises two anti-4-1BB on the same portion of the N-terminal arm. 4-1BB (CD137) induces IFNγ and proliferation of NK cells, promotes DC activation, but is best known as a co-stimulatory receptor on T cells that stimulates lymphokine secretion, enhances proliferation, and reduces sensitivity to activation induced cell death. (see pg. 1 line 23 through pg. 2 in line 13). 4-1BB stimulation on T cell is particularly relevant promoting to anti-tumor immunity. Id. Regarding instant claim 2, Figs 3 and 6 show results from a bispecific antibody bivalent for 4-1BB clone 20H4.9. Koller teaches a bispecific antigen binding molecule comprising four anti-4-1BB antigen binding domains comprising two heavy chains comprising VHCH1-peptide linker-VHCH1, relating to instant claim 4. Regarding instant claim 5, see peptide linkers on pg. 98, particularly SEQ ID NOs: 110, 114, and 115. Regarding instant claims 49-52, Koller on pg. 13 in lines 4-5 teaches a polynucleotide encoding the bispecific antibody. The polynucleotide is maintained in host cells including CHO cells, relating to instant claims 53-54 (see pg. 44 in lines 20-22 and pg. 46 in lines 2-6). Relating to instant claim 55, Koller teaches a method of producing a bispecific antigen binding molecule on pg. 80 in lines 18-24. Regarding instant claim 48, Koller teaches in claim 39 a pharmaceutical composition comprising a bispecific antibody with an excipient.
It would have been prima facie obvious to a person of ordinary skill in the art to use the anti-CD38 binding taught by ‘588 bispecific as the binding site targeting a cell antigen of Koller’s bispecific anti-4-1BB. The skilled artisan would have been motivated because the combination of targeting 4-1BB and CD38 was suggested in the art to be used in a bispecific antibody (see Xu ¶ [0089] on pg. 25 spanning pg. 26). Therefore, in view of the level of ordinary skill and design incentives to create bispecific antibodies that activate T cells and target T cells to a CD38+ tumor, the skilled artisan would have had the motivation to combine ‘588’s teachings anti-CD38 binding site with an anti-4-1BB binding arm comprising two binding sites as taught by Koller, and the ordinarily skilled person would have arrived at the instantly claimed invention with a reasonable expectation of success in doing so.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 3, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71-96, 98-102, and 104-107 of copending Application No. 18/420,588 in view of Koller in WO 2018/127473 A1 published on July 12, 2018 and Xu in WO 2018/107069 A1 published June 14, 2018; as applied to claims 1-2, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 above and further in view of Keyt in WO 2018017761 A1 published January 25, 2018.
See ‘588 in view of Koller and Xu as applied to claims 1-2, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 above.
While ‘588 in view of Koller and Xu teaches a bispecific antibody comprising an anti-CD38 binding arm and an anti-4-1BB antigen binding arm with two binding site, ‘588 in view of Koller and Xu does not teach that the anti-4-1BB binding sites bind to different epitopes on 4-1BB.
The prior art contained a "base" device (method, or product) upon which the claimed invention can be seen as an "improvement."
Koller teaches that the tetravalent embodiment of the 4-1BB binding arm comprising multiple anti-4-1BB had decreased mean fluorescent intensity (MFI) due to internal competition for 4-1BB-specific epitopes (pg. 136 in lines 22-23). The tetravalent construct of Koller used the same antigen-binding domain, 20H4.9, which binds the same epitope, which Koller teaches is the reason that the tetravalent construct had less favorable properties. Thus, Koller teaches a base device upon which the claimed invention described in claim 3 is an improvement upon because it solves the problem of Koller by binding to different epitopes on 4-1BB.
The prior art contained a "comparable" device (method, or product that is not the same as the base device) that has been improved in the same way as the claimed invention.
Keyt teaches multimeric agonistic anti-4-1BB binding molecules comprising multiple anti-4-1BB binding domains that bind to bind to two or more different 4-1BB epitopes (see pg. 3 in ¶ [0011]; see also claim 11).
One of ordinary skill in the art could have applied the known "improvement" technique in the same way to the "base" device (method, or product) and the results would have been predictable to one of ordinary skill in the art.
It was within the level of skill in the art at the time of instant filing to use anti-4-1BB binding sites that bind different epitopes of anti-4-1BB in the construction of a bispecific antibody of ‘332 in view of Koller. Given the ordinary level of skill and the evidence of record, the skilled artisan would have had a reasonable expectation of success at arriving at the bispecific antigen binding molecule of claim 3.
"It's enough … to show that there was a known problem … in the art, that [another reference] … helped address that issue, and that combining the teachings of [the two references] wasn't beyond the skill of an ordinary artisan. Nothing more is required to show a motivation to combine under KSR." See Intel Corp. v. PACT XPP Schweiz AG, 61 F.4th 1373, 1380-81, 2023 USPQ2d 297 (Fed. Cir. 2023) In conclusion, it would have been prima facie obvious to a person of ordinary skill in the art to modify the bispecific antibody of ‘588 in view of Koller and Xu to have multiple 4-1BB binding sites that bind different epitopes of 4-1BB as suggested by Keyt.
Claims 1-2, 4-5, 8-12, 33-34, 35, 36, 48-55, 57, and 59-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71-96, 98-102, and 104-107 of copending Application No. 18/420,588 in view of Koller in WO 2018/127473 A1 published on July 12, 2018 and Xu in WO 2018/107069 A1 published June 14, 2018; as applied to claims 1-2, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 above and further in view of Brinkmann et al. mAbs. 2017. 9(2):182-212.
See ‘588 in view of Koller and Xu as applied to claims 1-2, 4-5, 8-12, 33-34, 36, 48-55, 57, and 59-60 above.
While ‘588 in view of Koller and Xu teaches a bispecific antibody comprising an anti-CD38 binding arm and an anti-4-1BB antigen binding arm with two binding site, ‘588 in view of Koller and Xu does not teach the mutations H435R and Y436F.
However, Brinkmann teaches that purification of bispecific antibodies can be improved by introducing H435A and Y436F mutations into one of the two heavy chains of a bispecific antibody (see pg. 192 in the first ¶ of the second col.). The mutations ablate the ability of protein A to bind to the heavy chain. Therefore, dimers of two heavy chain having the mutation, which do not form a bispecific antibody, cannot be purified by protein A chromatography, but dimers of one heavy chain having the mutations with one not having the mutations can be purified and are bispecific.
It would have been prima facie obvious to the skilled artisan to construct the bispecific anti-CD38 x anti-41BB antibody of ‘588 in view of Koller and Xu using the method for enhancing purification by introducing H435A and Y436F mutations into one of the two heavy chains. The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). Brinkmann explicitly teaches that there was an advantage to the aforementioned mutational strategy, therefore the skilled artisan would have been motivated to make the modification of introducing H435A and Y436F mutations into a heavy chain of ‘588 in view of Koller and Xu’s anti-CD38 x anti-41BB antibody. Given that each antibody has a limited number of heavy chains (two), it would have been prima facie obvious to try the second heavy chain, i.e. a heavy chain having the 4-1BB targeting arm. In view of the level of ordinary skill in the art and explicit teachings, the skilled artisan would have a reasonable expectation of success. Therefore, it would have been obvious to a person of ordinary skill to construct the bispecific anti-CD38 x anti-41BB antibody of ‘588 in view of Koller and Xu using the method for enhancing purification by introducing H435A and Y436F mutations into a heavy chain comprising the anti-4-1BB binding sites.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Copending 18/766,802 and 19/372,768 comprise subject matter directed to the anti-4-1BB antigen binding domain having HCVR CDRs 12-14-16 and, pertaining to ‘802 alone, CDRs 74-76-78. The instant claims may be subject to non-statutory double patenting rejections over ‘802 and ‘768 when examination is expanded to non-elected species.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANNA K SWARTWOUT whose telephone number is (703)756-4672. The examiner can normally be reached Monday-Friday 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet Epps-Smith can be reached at (571) 272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/B.K.S./Examiner, Art Unit 1644
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683