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 .
Election/Restrictions
Applicant’s election without traverse of species (A) method of inhibiting tumor growth for method, (B) interferon g as cytokine, (C) SEQ ID NO: 77 as DOTA amino acid sequence, (D) GD2 as additional target antigen, (E) SEQ ID NO: 7 as VH amino acid sequence, (F) SEQ ID NO: 82 as heavy chain amino sequence, (G) chemotherapy as additional cancer therapy, (h) pembrolizumab as immune checkpoint inhibitor, (I) anti-Ly6C antibody as non-checkpoint inhibitor therapy, and (J) neuroblastoma as cancer type in the reply filed on June 30, 2026 is acknowledged.
Claim 32 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1, 3, 5, 7, 9, 15, 17, 20, 22-30, 34, and 36 are under consideration in this office action.
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 application is the national stage entry of PCT/EP2018/079931, which claims benefit to U.S. Provisional Application No. 63/171,304, filed April 6, 2021.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on October 5, 2023 and April 14, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
Recommendations
Claims 1, 9, 15, 17, 20, and 30 use the term “optionally”. Applicant is advised that limitations after “optionally” do not have patentable weight. Review and confirm that this usage of the term was intentional.
Claim Objections
Claim 5 is objected to because of the following informalities:
Claim 5 recites incorrectly “the first second effective dose” in line 3. This should be amended to be “the first effective dose”.
Appropriate correction is required.
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.
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.
Claim 15 is 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.
Regarding claim 15, the term "optionally" in line 2 renders the claim indefinite because it is unclear whether the limitations following the term directed to different cytokines are part of the claimed invention or merely set forth as possible examples. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112(a)
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.
Written Description
Claims 1, 3, 5, 7, 9, 15, 17, 20, 22-24, 26-30, 34, and 36 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.
“[T]he 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.
Claims 1 ,3, 5, 7, 9, 15, 17, 20, 22, 23-24, 26-30, 34, and 36 are drawn to a multi-specific antibody comprising a CD3 binding domain; the additional domains and their target are left undefined, and these other antibody arms read on any antibody with binding to any other antigen. Claim 20 is limited to anti-CD3 multi-specific antibodies that bind another target antigen, but this is not sufficient for written description purposes, because these antigen binding domains are defined only by function. Although the multispecific antibody of claim 23 targets GD2, this antibody may comprise additional domains with undefined targets.
Claim 23 is drawn to a multi-specific antibody comprising a CD3 binding domain and a GD2 binding domains. Although the six CDRs of the CD3 binding domain is sufficiently described (as set forth in claim 1), the GD2 binding domain may comprise additional amino acid variants within the heavy and light chains. As such, claim 23 encompass a vast genus of anti-GD2 antibodies comprising one or more conservative amino acid substitutions within the CDRs of the antigen binding domain.
As detailed below, applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus of GD2 binding domains, and as such, applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
Antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three complementarity determining regions that provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see Almagro et al, Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1; instant PTO-892).
The art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. See for example Kussie (instant PTO-892), who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-azophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (see abstract).
Furthermore, 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).
As another example, see Chen et al., 1995 (instant PTO-892), which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody. See also Koenig 2017 (instant PTO-892), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. Looking at figure 1 of Koenig, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning a complete loss of binding ability. In VH-CDR2, for example, mutating any given residue to cysteine, resulted in reduced binding at 12 residues and a complete loss of binding at 5 residues. That is, at 100% of the positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target. Looking at a specific position, in 100% of the mutations of residue 55, binding was reduced (15/19) or eliminated (4/19). While residues 56-65 appear more tolerant of change, residues 50-55 are generally intolerant of change.
It is appreciated that Koenig is studying one specific antibody and there is no evidence that the instant antibodies would react in the same way. However, this is part of the problem. It is entirely unclear from the specification which residues of Applicant’s CDRs are tolerant or intolerant to change, and whether those tolerant positions are only tolerant to conservative mutations. The fact that some residues might tolerate mutation does not convey to the skilled artisan that Applicant knew which of the claimed residues were tolerant of such, i.e. does not convey that Applicant was in possession of those sequences that are mutated yet preserve the claimed function. The specification fails to convey possession of an invention commensurate in scope with what is now claimed and therefore fails to meet the written description requirement.
Making changes to the CDR sequences of an antibody is a highly unpredictable process, and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions. Without this guidance or direction, the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed does not sufficiently describe the genus of the other antigen binding domains or the GD2 binding domain with variation as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
To satisfy the written description requirement, a patent 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.
In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of antigen binding domains or genus of anti-GD2 antibodies encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art, as evidenced by Edwards et al., 2003 (instant PTO-892), teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
For claims drawn to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011). An antibody described only by functional characteristic, such as antibody that binds GD2, as in claim 20, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995).
With the exception of specifically disclosed antibodies with specific CDRs, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, 1, 3, 5, 7, 9, 15, 17, 20, 22-24, 26-30, 34, and 36 do not meet the written description requirement.
Scope of Enablement
Claims 1, 3, 5, 7, 9, 15, 17, 20, 22-30, 34, and 36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating neuroblastoma with the anti-CD3 multi-specific antibody of claim 25, does not reasonably provide enablement for the treatment of any cancer comprising the anti-CD3 multi-specific antibody of the other claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Case law holds that applicant’s specification must be “commensurately enabling [regarding the scope of the claims].” See Ex Parte Kung, 17 USPQ2d 1545, 1547 (Bd. Pat. Appl. Inter. 1989). Otherwise undue experimentation would be involved in determining how to practice and use applicant’s invention. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described in In re Colianni, 195 USPQ 150 (CCPA 1977) and have been adopted by the Board of Patent Appeals and Interferences in Ex Parte Forman, 230 USPQ 546 (BPAI 1986). Among these factors are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the breath of the claims,
5. the amount of direction or guidance present, and
6. the presence or absence of working examples.
The following is an analysis of these factors in relationship to this application.
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the methods of claims 1, 3, 5, 7, 9, 15, 17, 20, 22-30, 34, and 36 is that the anti-CD3 bispecific antibody is a treatment for any cancer. Therefore, the claims are directed to the treatment of cancer using a broad range of multi-specific antibodies comprising at least CD3 binding domain and treatment of all cancer types.
Anti-CD3 antibodies are expressed on the surface of T cells and are used in bispecific formats to recruit patient T cells to attack specific malignancies, which is dependent on the target of the other arm. For example, an anti-CD3 multispecific antibody that also binds HER2 would be expected to have efficacy against cancers expressing HER2 (see US 20190359732 [0005], published November 28, 2019; instant PTO-892). Accordingly, an anti-CD3 multi-specific antibody that binds HER2 would not be expected to be efficacious in a cancer not expressing HER2.
According to the specification, administration of anti-CD3/anti-GD2 bispecific antibodies to a neuroblastoma PDX mouse model affected tumor growth and was associated with increased survival (Figure 7). As such, the specification supports the use of anti-CD3/anti-GD2 bispecific antibodies for the treatment of neuroblastoma.
The instant specification is not fully enabling for claims 1, 3, 5, 7, 9, 15, 17, 20, 22-30, 34, and 36 because one cannot follow the guidance presented therein, or within the art at the time of filing, and predictably practice the claimed methods without engaging in extensive and undue experimentation. Given that the nature of the invention is in vivo treatment of cancer, a person having ordinary skill in the art would have to perform multiple further in vivo experiments, in animals and/or human subjects, in order to demonstrate whether various anti-CD3 multispecific antibodies of the invention could or could not be used. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation for treating any disorder related to cancer or immune-related disease.
Therefore, in light of the above factors, it is seen that undue experimentation would be necessary to use the invention of claim 1 in the method claims 1, 3, 5, 7, 9, 15, 17, 20, 22-30, 34, and 36 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 7, 9, 15, 17, 20, 22, 28-30, 34, and 36 are rejected under 35 U.S.C. 103 as being unpatentable US 20190359732, published November 28, 2019 (“Cheung”; instant PTO-892) in view of WO 202004738, published March 5, 2020 (“Brownstein”; IDS from 10/5/2023).
The claims are drawn to a method for treating cancer or inhibiting tumor growth comprised of administering an anti-CD3 multi-specific antibody and dexamethasone, wherein the multispecific antibody comprises two heavy chains, two light chains, and two scFv attached to each respective light chain.
Cheung et al teaches an anti-CD3 multi-specific antibody (HER2-BsAB) comprising two heavy chains, two light chains, and two scFvs (see Figure 1A, shown below), which is the same format for the multi-specific antibody set forth in claims 1 and 17.
PNG
media_image1.png
379
504
media_image1.png
Greyscale
The scFv huOKT3 is an anti-CD3 binding domain comprised of VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65 [0099], which are identical to instant VH of SEQ ID NO: 7 and instant VL of SEQ ID NO: 33 of claim 22. The huOKT3 of VH of SEQ ID NO: 64 comprises VH-CDR1-3 of instant SEQ ID NOs: 1-3 and VL-CDR1-3 of instant SEQ ID NOs: 4-6, as in the CD3 binding domain of claim 1. The multispecific antibody bind the additional target HER2, as in claim 20.
Cheung teaches a method of treating a patient diagnosed with cancer, including neuroblastoma, comprising administering the multispecific antibody ([0005],[0010],[0273]), as in claims 1, 3, 34, and 36. Cheung teaches a method of treating cancer comprising administering a therapeutically effective amount of an ex vivo cell comprising a vector expressing the multispecific antibody ([0021,[0038)], as in claims 3, 7; the T cells are autologous [0047], as in instant claim 9. The mixture of T cells is cryopreserved [0218], as in claim 9. The method of administering may be intravenous, intraperitoneal, subcutaneous, or intramuscular [0203], as in instant claim 26. The multispecific antibody of Cheung may be delivered in combination with a cytokine [0288], as in claim 15, or a chemotherapy [0049], as in claim 30.
Cheung teaches that the resulting cytokine release syndrome (CRS) still poses costly and often life-threatening complications. Importantly, despite the ability of bispecific antibodies to activate T cells, the same inhibitory pathways that regulate classic T cell function might still limit their effectiveness [0331], providing motivation to decrease cytokine release syndrome. Cheung does not teach administration of dexamethasone with the multispecific antibody for amelioration of cytokine release syndrome.
Brownstein teaches strategies to mitigate cytokine release syndrome associated with CD3 multispecific antibodies (abstract; [0030]), these include the administration of dexamethasone [0104], as in instant claim 1. The method comprises administering dexamethasone 1 hour before administration of the first and second doses of the antibody [0104], where the second dose is administered within 24-96 hours after the first dose [0096], as in claims 3, 7, and 28-29. This cycle is repeated at least one more time (claim 78 of Brownstein), as in claims 3 and 7.
Given that Cheung teaches a method for treating comprising administration of an anti-CD3 multispecific antibody of the claimed antibody format and the claimed CD3 binding domain and further given that Brownstein teaches a method of mitigating cytokines release syndrome associated with administration of anti-CD3 multispecific antibodies, it would have been obvious to one of ordinary skill in the art to modify the method of treating cancer of Cheung by adding dexamethasone. This is because dexamethasone is an anti-inflammatory agent known in the art to be useful for decreasing adverse events associated with administration of T cell activators, like the claimed anti-CD3 multispecific antibody. Such would amount to the use of a known technique to a known method (i.e. adding dexamethasone to anti-CD3 multispecific antibody therapy) ready for improvement to yield predictable results (i.e. improving therapeutic response to anti-CD3 multispecific antibody therapy). See MPEP2143.
Claims 1, 3, 5, 7, 9, 15, 17, 20, 22, 28-30, 34, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190359732 (“Cheung”) in view of WO 202004738 (“Brownstein”), as applied to claims 1, 3, 7, 9, 15, 17, 20, 22, 28-30, 34, and 36 above, and further in view of US 20190092862, published March 28, 2019 (“Cui”, instant PTO-892).
The teachings of Cheung in view of Brownstein are discussed above; these references do not teach the doses of dexamethasone of instant claim 5.
Cui teaches a method for the treatment of cancer comprising administration of anti-CD3 multispecific antibody in combination with dexamethasone at a dose from 0.1-5 mg/kg ([0012];[0021]), which overlaps with the dose range of instant claim 5.
Given that Cheung in view of Brownstein teach a method of treating cancer comprising administration of an anti-CD3 multispecific antibody and dexamethasone, and further given that Cui teaches a dose of dexamethasone that overlaps with the dose of instant claim 5, it would have been obvious to one of ordinary skill in the art to apply the dexamethasone dose of Cui in the method of Cheung in view of Brownstein and have a reasonable expectation of successfully treating cancer. This is because known work in one field of endeavor (the dose of Cui) may prompt variation of it for use in either the same field based on design incentives. See MPEP 2143.
Claims 1, 3, 7, 9, 15, 17, 20, 22-25, 28-30, 34, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190359732 (“Cheung”) in view of WO 202004738 (“Brownstein”), as applied to claims 1, 3, 7, 9, 15, 17, 20, 22, 28-30, 34, and 36 above, and further in view of US 20130216528, published June 20, 2011 (“Ahmed”, instant PTO-892).
The teachings of Cheung in view of Brownstein are discussed above; these references do not teach the sequences of instant claims 23-25.
The CD3 multi-specific antibody of claim 23 is comprised of heavy chain of SEQ ID NO: 82 and light chain SEQ ID NO: 81. Instant SEQ ID NO: 82 comprises the heavy chain of the anti-GD2 antibody Hu3F8; instant SEQ ID NO: 81 comprises the light chain of the anti-GD2 antibody Hu3F8, a linker, and the anti-CD3 scFv huOKT3.
Cheung teaches a light chain of the multispecific antibody comprised of the light chain of the anti-HER2 antibody, a linker, and the anti-CD3 scFv of huOKT3; this is SEQ ID NO: 47 of Cheung.
Regarding claims 23-24, Ahmed teaches the anti-GD2 antibody Hu3F8, which is a humanized form of 3F8 [0006]. The Ahmed antibody has a heavy chain of SEQ ID NO: 4 [0016], which comprises the same heavy chain variable domain of the GD2 binding domain of instant SEQ ID NO: 82, and a light chain of SEQ ID NO: 5 [0018], which is the Hu3F8 light chain of instant SEQ ID NO: 81. Ahmed teaches the same anti-GD2 binding domain of claims 23 and 24. Ahmed also teaches a bispecific antibody comprising anti-GD2 antibody and a second antigen binding site for CD3 (Ahmed claim 25).
Instant claim 25 is drawn to a multispecific antibody of first light chain (SEQ ID NO: 99), first heavy chain (SEQ ID NO: 100), second light chain (SEQ ID NO: 101), and second heavy chain (SEQ ID NO: 102). The first light chain is light chain of hu3F8 fused to huOKT3 scFv and the first heavy chain is the heavy chain of hu3F8, which Cheung teaches. The second light chain is the light chain of hu3F8, which Cheung teaches, and an scFv huC825. Cheung teaches C825 is a murine scFv antibody that binds DOTA [0299], as in the second light chain of claim 25. The second heavy chain is the heavy chain of hu3F8, which Cheung teaches.
Given that Cheung teaches a multispecific antibody comprising anti-CD3 scFv and a second antigen binding domain directed to a different target, and further given that Ahmed teaches a bispecific anti-GD2/anti-CD3 antibody, it would have been obvious to one of ordinary skill in the art to substitute the anti-GD2 antibody of Ahmed in the multispecific antibody format of Cheung. Such would amount to the simple substitution of one known element for another to obtain predictable results. See MPEP 2143.
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, 3, 5, 7, 9, 15, 17, 20, 22-30, 34, and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,820,832 in view of WO 202004738, published March 5, 2020 (“Brownstein”), US 20190092862, published March 28, 2019 (“Cui”), and US 20130216528, published June 20, 2011 (“Ahmed”). Although the claims at issue are not identical, they are not patentably distinct from each other because they are both drawn to a method of treating cancer comprising administering an anti-CD3 multispecific antibody two heavy chains and two light chains, wherein the light chain is fused to a scFv.
The scFv of claim 1 of ‘832 is comprised of VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65 [0099], which are identical to instant VH of SEQ ID NO: 7 and instant VL of SEQ ID NO: 33 of claim 22. The VH of SEQ ID NO: 64 comprises VH-CDR1-3 of instant SEQ ID NOs: 1-3 and VL-CDR1-3 of instant SEQ ID NOs: 4-6, as in the CD3 binding domain of claim 1. ‘832 teaches a light chain of the multispecific antibody comprised of the light chain of the anti-HER2 antibody, a linker, and the anti-CD3 scFv of huOKT3; this is SEQ ID NO: 47 of claims 7-8 of ‘832.
Brownstein teaches strategies to mitigate cytokine release syndrome associated with CD3 multispecific antibodies (abstract; [0030]), these include the administration of dexamethasone [0104], as in instant claim 1. The method comprises administering dexamethasone 1 hour before administration of the first and second doses of the antibody [0104], where the second dose is administered within 24-96 hours after the first dose [0096], as in claims 3, 7, and 28-29. This cycle is repeated at least one more time (claim 78 of Brownstein), as in claims 3 and 7.
Cui teaches a method for the treatment of cancer comprising administration of anti-CD3 multispecific antibody in combination with dexamethasone at a dose from 0.1-5 mg/kg ([0012];[0021]), which overlaps with the dose range of instant claim 5.
Regarding claims 23-24, Ahmed teaches the anti-GD2 antibody Hu3F8, which is a humanized form of 3F8 [0006]. The Ahmed antibody has a heavy chain of SEQ ID NO: 4 [0016], which comprises the same heavy chain variable domain of the GD2 binding domain of instant SEQ ID NO: 82, and a light chain of SEQ ID NO: 5 [0018], which is the Hu3F8 light chain of instant SEQ ID NO: 81. Ahmed teaches the same anti-GD2 binding domain of claims 23 and 24. Ahmed also teaches a bispecific antibody comprising anti-GD2 antibody and a second antigen binding site for CD3 (Ahmed claim 25).
Given that the claims of ‘832 teach a method for treating comprising administration of an anti-CD3 multispecific antibody of the claimed antibody format and the claimed CD3 binding domain and further given that Brownstein teaches a method of mitigating cytokines release syndrome associated with administration of anti-CD3 multispecific antibodies, it would have been obvious to one of ordinary skill in the art to modify the method of treating cancer of ‘832 by adding dexamethasone using the dose of Cui and the VH and VL sequences of Ahmed. This is because dexamethasone is an anti-inflammatory agent known in the art to be useful for decreasing adverse events associated with administration T cell activators, like the claimed anti-CD3 multispecific antibody. Such would amount to the use of a known technique to a known method (i.e. adding dexamethasone to anti-CD3 multispecific antibody therapy) ready for improvement to yield predictable results (i.e. improving therapeutic response to anti-CD3 multispecific antibody therapy). See MPEP2143.
Claims 1, 3, 5, 7, 9, 15, 17, 20, 22-30, 34, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 4, 9-10, 14, 21, 26, 28, 30, 33, 36, 38, 45-46, 48, 51, 56-57, and 60 of copending Application No. 18/007,292 in view of WO 202004738, published March 5, 2020 (“Brownstein”), US 20190092862, published March 28, 2019 (“Cui”), and US 20130216528, published June 20, 2011 (“Ahmed”). Although the claims at issue are not identical, they are not patentably distinct from each other because they are both drawn to a method of treating cancer comprising administering an anti-CD3 multispecific antibody two heavy chains and two light chains, wherein the light chain is fused to a scFv.
The ex vivo armed T cell of ‘292 claim 1 that is coated with an anti-CD3 multi-specific antibody is comprised of VH-CDR1-3 of instant SEQ ID NOs: 1-3 and VL-CDR1-3 of instant SEQ ID NOs: 4-6, which is identical to the CD3 binding domain of instant claim 1. Claim 48 of ‘292 is drawn to a method of treating cancer comprising administering the ex vivo armed T cell.
Brownstein teaches strategies to mitigate cytokine release syndrome associated with CD3 multispecific antibodies (abstract; [0030]), these include the administration of dexamethasone [0104], as in instant claim 1. The method comprises administering dexamethasone 1 hour before administration of the first and second doses of the antibody [0104], where the second dose is administered within 24-96 hours after the first dose [0096], as in claims 3, 7, and 28-29. This cycle is repeated at least one more time (claim 78 of Brownstein), as in claims 3 and 7.
Cui teaches a method for the treatment of cancer comprising administration of anti-CD3 multispecific antibody in combination with dexamethasone at a dose from 0.1-5 mg/kg ([0012];[0021]), which overlaps with the dose range of instant claim 5.
Regarding claims 23-24, Ahmed teaches the anti-GD2 antibody Hu3F8, which is a humanized form of 3F8 [0006]. The Ahmed antibody has a heavy chain of SEQ ID NO: 4 [0016], which comprises the same heavy chain variable domain of the GD2 binding domain of instant SEQ ID NO: 82, and a light chain of SEQ ID NO: 5 [0018], which is the Hu3F8 light chain of instant SEQ ID NO: 81. Ahmed teaches the same anti-GD2 binding domain of claims 23 and 24. Ahmed also teaches a bispecific antibody comprising anti-GD2 antibody and a second antigen binding site for CD3 (Ahmed claim 25).
Given that the claims of ‘292 teach a method for treating comprising administration of an anti-CD3 multispecific antibody of the claimed antibody format and the claimed CD3 binding domain and further given that Brownstein teaches a method of mitigating cytokines release syndrome associated with administration of anti-CD3 multispecific antibodies, it would have been obvious to one of ordinary skill in the art to modify the method of treating cancer of ‘292 by adding dexamethasone using the dose of Cui and the VH and VL sequences of Ahmed. This is because dexamethasone is an anti-inflammatory agent known in the art to be useful for decreasing adverse events associated with administration T cell activators, like the claimed anti-CD3 multispecific antibody. Such would amount to the use of a known technique to a known method (i.e. adding dexamethasone to anti-CD3 multispecific antibody therapy) ready for improvement to yield predictable results (i.e. improving therapeutic response to anti-CD3 multispecific antibody therapy). See MPEP2143.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST).
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, Jeffrey Stucker can be reached at (571)272-0911. 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.
Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/ Examiner, Art Unit 1675
Prosecution Insights