Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of the Claims
1. Claims 1-34 are the original claims filed on 11/27/2023. Claims 1-34 are all the claims.
Priority
2. USAN 18/520,308 filed, 11/27/2023, is a Divisional of 15/951,137, filed 04/11/2018, now U.S. Patent # 11866507, and having 3 RCE-type filing therein,
15/951,137 Claims Priority from Provisional Application 62/484,217, filed 04/11/2017.
Information Disclosure Statement
3. As of 7/21/20206, a total of one (1) IDS is filed: 9/13/2024. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Drawings
4. The drawing sheet for Figures 21A, 21B, 22C, 22F, 29C, 29F, 30, 34A-H, are objected to because the use of the term DART, which is a trade name or a mark used in commerce, has been noted. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
5. The disclosure is objected to because of the following informalities:
a) The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See [0223]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
b) The use of the term, e.g., CellTiterGlo, Bio-Glo, CremophorEL, DART, which is a trade name or a mark used in commerce, has been noted in this application. It should be capitalized wherever it appears and be accompanied by the generic terminology. Applicants are requested to review the entire specification for any other improper citations besides those noted herein above.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
6. Claims 1-34 are objected to because of the following informalities:
a) Claims 1-34 recite “antigen binding domain” and “antigen-binding domain.” One or the other but not both is preferable.
b) Amend claim 2 to recite “anti-CD3dsFv” or “anti-CD3 dsFv.” One or the other but not both is preferable.
c) Amend claim 9 to recite “CD3 epsilon (CD3ε).”
d) Amend claim 10 to recite “binds to the TAA selected from…” in order to comport with claim 1.
e) Amend claim 10 to delete redundancy for: CD132 or (IL2RG) since each of the terms reference the same protein, i.e., IL-2 receptor subunit gamma; and CEACAM5 or (CEA) since each of the terms reference the same protein, i.e., carcinoembryonic antigen-related cell adhesion molecule 5.
f) Amend claim 10 to recite “(Fc[e]εRI)”.
g) Amend claim 12 to recite “a second antigen binding domain, wherein.”
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.
7. Claims 1-14 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.
a) Claims 1-14 are confusing as to the relationship of the “opposite polypeptides” in claim 1 to the 1st and 2nd polypeptides of claim 2. Clarification is requested how the multispecific polypeptide construct of claim 1 compares to the 1st and 2nd polypeptides for “a multispecific polypeptide construct” of claim 2. Otherwise, claim 2 seemingly comprises an additional multispecific polypeptide construct to that of claim 1.
b) A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
i) In the present instance, claim 10 recites the broad recitation “IgE Receptor”, and the claim also recites “(FceRI)”, which is the narrower statement of the range/limitation. Should applicants amend the claim to recite “(FceRI)”, then further amendment of the term is required under MPEP § 2173.05(d), e.g., [ε RI).
ii) In the present instance, claim 10 recites the broad recitation “VEGF”, and the claim also recites “VEGF-A, VEGF-B, VEGF-C, VEGF-D” and “P1GF”, which is the narrower statement of the range/limitation.
iii) In the present instance, claim 10 recites the broad recitation “Jagged Ligands”, and the claim also recites “Jagged 1, Jagged 2”, which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
c) Regarding claim 10, the term “(Lewis A)” renders the claim indefinite because it is unclear whether the limitation(s) within the parentheses is part of the claimed invention. See MPEP § 2173.05(d).
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
8. Claims 1-34 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim construction
Claims 1-34 are interpreted as comprising polynucleotides encoding multispecific polypeptides having an CD3 binding domain comprising a VH linked to an Fc region, a VL linked to an Fc region, where the VH and VL are linked to form a dscfv, the Fc regions are heterodimeric, respectively, and where one or both of the VH-VL or the heterodimeric Fc regions comprises at least a binding domain for a TAA.
“polynucleotide”: the specification defines an “isolated polynucleotide” as one more properly that encompasses the engineered construct of the invention at:
[0182] The term “isolated polynucleotide” as used herein shall mean a polynucleotide of genomic, cDNA, or synthetic origin or some combination thereof, which by virtue of its origin the “isolated polynucleotide” (1) is not associated with all or a portion of a polynucleotide in which the “isolated polynucleotide” is found in nature, (2) is operably linked to a polynucleotide that it is not linked to in nature, or (3) does not occur in nature as part of a larger sequence. Polynucleotides in accordance with the disclosure include the nucleic acid molecules encoding the heavy chain immunoglobulin molecules shown herein, and nucleic acid molecules encoding the light chain immunoglobulin molecules shown herein.
The POSA could reasonably assume the polynucleotide is genetically engineered but not necessarily isolated. The POSA could reasonably assume the polynucleotide is required to be of such a nature as to accommodate nucleic acids encoding both a heavy and light chain of an antibody.
“heterodimeric Fc”: the specification teaches the meaning and examples of the phrase as modifications
[0025] In some embodiments, the Fc is a heterodimeric Fc. In some cases, one or both Fc polypeptides of the heterodimeric Fc region comprises at least one modification to induce heterodimerization compared to a polypeptide of a homodimeric Fe region, optionally compared to the Fc polypeptide set forth in SEQ ID NO:1 or an immunologically active fragment thereof. In some embodiments, each of the Fc polypeptides of the heterodimeric Fc independently comprise at least one amino acid modification. In some cases, each of the Fc polypeptides of the heterodimeric Fc comprise a knob-into-hole modification or comprise a charge mutation to increase electrostatic complementarity of the polypeptides. In some examples, the amino acid modification is a knob-into-hole modification.
[0026] In some embodiments, the first Fc polypeptide of the heterodimeric Fc comprises the modification selected from among Thr366Ser, Leu368Ala, Tyr407Val, and combinations thereof and the second Fc polypeptide of the heterodimeric Fc comprises the modification T366W. In some cases, the first and second Fc polypeptides further comprise a modification of a non-cysteine residue to a cysteine residue, wherein the modification of the first polypeptide is at one of a position Ser354 and Y349 and the modification of the second Fc polypeptide is at the other of the position Ser354 and Y349.
[0027] In some examples, the amino acid modification is a charge mutation to increase electrostatic complementarity of the polypeptides. In some embodiments, the first and/or second Fc polypeptides comprise a modification in complementary positions, wherein the modification is replacement with an amino acid having an opposite charge to the complementary amino acid of the other polypeptide. In some embodiments, the first or second polypeptide comprise a modification in complementary positions, wherein the modification is replacement with an amino acid having an opposite charge to the complementary amino acid of the other polypeptide. In some embodiments, at least the first or second Fc polypeptides each comprise a modification in a complementary position, wherein the modification is replacement with an amino acid having an opposite charge to the complementary amino acid of the other polypeptide. In some embodiments, the first and second Fc polypeptides each comprise a modification in complementary positions, wherein the modification is replacement with an amino acid having an opposite charge to the complementary amino acid of the other polypeptide.
[0028] In some embodiments, one of the first or second Fc polypeptide of the heterodimeric Fc further comprises a modification at residue Ile253. In some instances, the modification is Ile253Arg. In some embodiments, one of the first or second Fc polypeptide of the heterodimeric Fc further comprises a modification at residue His435. In some instances, the modification is His435Arg. In some embodiments, the Fc region comprises a polypeptide that lacks Lys447.
[0029] In some embodiments, modifications within the Fc region reduce binding to Fc-receptor-gamma receptors while having minimal impact on binding to the neonatal Fc receptor (FcRn). In some embodiments, the mutated or modified Fc polypeptide includes the following mutations: Met252Tyr and Met428Leu or Met252Tyr and Met428Val (M252Y, M428L, or M252Y, M428V) using the Kabat numbering system.
None of the claims include a modification to any one of the Fc regions that qualifies as contributing to a heterodimeric feature. The POSA could reasonably conclude that an Fc heterodimer comprises attenuated or swapped constant region domains within an Fc region (e.g., deletion of a CH1, CH2 and/or CH3 domain) or Ig isotype-swapped constant regions (e.g., exchanging an IgM CH2 for a IgG1 CH2), but the specification does not suggest any such domain modifications. The breadth and scope of the heterodimer for an Fc region exceeds what is taught in the specification.
“CD3-binding region”: the specification teaches an example of a CD3 binding region or anti-CD3 antibody at
[0601] “… and other CD3-binding regions, including other anti-CD3 antibodies, including dsFv or other monovalent fragments;…”
[0067] In some of any of the provided embodiments, the anti-CD3 antibody or antigen-binding fragment comprises a VH CDR1 comprising the amino acid sequence TYAMN (SEQ ID NO: 16); a VH CD2 comprising the amino acid sequence RIRSKYNNYATYYADSVKD (SEQ ID NO: 17); a VH CDR3 comprising the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO: 18), a VL CDR1 comprising the amino acid sequence RSSTGAVTTSNYAN (SEQ ID NO: 19); a VL CDR2 comprising the amino acid sequence GTNKRAP (SEQ ID NO: 20); and a VL CDR3 comprising the amino acid sequence ALWYSNLWV (SEQ ID NO: 21).
[0068] In some embodiments, the anti-CD3 dsFv comprises: a VH having the amino acid sequence of any of SEQ ID NOS: 14, 44, and 32-62 or a sequence that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of SEQ ID NOS: 14, 44, and 32-62; and a VL having the amino acid sequence of any of SEQ ID NOS: 15, 72, and 63-81 or a sequence that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of SEQ ID NOS: 14, 44, and 32-62. In some cases, the anti-CD3 dsFv comprises the amino acid sequence of SEQ ID NO: 14 and the amino acid sequence of SEQ ID NO: 15. In some cases, the anti-CD3 dsFv comprises the amino acid sequence of SEQ ID NO: 44 and the amino acid sequence of SEQ ID NO: 72.
[0601] Polynucleotides encoding at least a first polypeptide chain and a second polypeptide chain of the heterodimeric multispecific polypeptide construct were generated and cloned into a plasmid for expression. The first polypeptide chain generally included in order, from the N-terminus to C-terminus, an Fc hole polypeptide (e.g. set forth in SEQ ID NO:83); a cleavable linker, such as one containing one or more substrate recognition sites for a protease; and a variable light (VL) domain of a dsFv anti-CD3 antibody (e.g. set forth in SEQ ID NO:72). The second polypeptide chain generally included in order, from the N-terminus to C-terminus, an Fc knob polypeptide (e.g. set forth in SEQ ID NO: 82); the same cleavable linker as the first polypeptide chain; and a variable heavy domain of a dsFv anti-CD3 antibody (e.g. set forth in SEQ ID NO:44).
The POSA could reasonably conclude that a limited number of anti-CD3 antibodies are applicable to the engineered construct of the instant claimed polynucleotides with respect to the overall structure/function correlation for the invention taken as a whole.
“antigen binding domain”: the specification teaches multiple structures that could comprise an antigen binding domain at:
[0056] In some of any of the provided embodiments, the antigen binding domain(s) results in monovalent, bivalent, trivalent, or tetravalent binding to the TAA. In some embodiments, the one or more antigen binding domains that bind TAA independently are selected from an sdAb, an scFv or a Fab. In some embodiments, the one or more antigen binding domains that binds a TAA is a TAA is a single chain molecule, such as a single chain antibody fragment containing a VH and a VL, for example an sdAb or an scFv. In some embodiments, at least one of the antigen binding domains is a Fab containing a first chain comprising a VH-CH1 (Fd) and a second chain comprising a VL-CL.
[0058] In some embodiments, the at least one of the antigen binding domain(s) is a Fab.
[0065] In some embodiments, each of the first antigen binding domain and the second antigen binding domain of the bispecific construct includes one or more copies of an antibody or an antigen-binding fragment thereof selected from the group consisting of a Fab fragment, a F(ab′)2 fragment, an Fv fragment, a scFv, a scAb, a dAb, a single domain heavy chain antibody, and a single domain light chain antibody.
The POSA could reasonably conclude that a limited number of antigen binding domain structures are applicable to the engineered construct of the instant claimed polynucleotides with respect to the overall structure/function correlation for the invention taken as a whole. However, the POSA could reasonably construe under the BRI standard non-antibody formats such as a mimetic (e.g., DARPins, affibodies, affitins, anticalins, avimers, kunitz domain peptides, adnectins, centyrins, Fynomers, IgNARs and monobodies), a super immunoglobulin protein, a scaffold protein, etc. where no support is provided in the specification.
The interpretation encompasses a genus of polynucleotides encoding a genus of mutlispecific polypeptide constructs beyond those taught in the specification. Because applicant seeks patent protection for all such polynucleotides encoding any such mutlispecific polypeptide constructs, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
Here, all of the claims encompass any polynucleotide encoding any one or more of the multispecific polypeptide constructs in which the structure for heterodimeric Fc region is not defined, the anti-CD3 dsFc variable domains for both VH and VL, including the complementarity determining regions (CDRs) are not defined, and the structure of the antigen binding domains are not defined but only by the antigen to which they bind or at least for dependent claim 10. Adequate written description for antibody structures to bind an antigen depends upon whether the specification provides adequate written description for the antigen. While a specification may enable making a genus of antibodies, this does not necessarily place applicant in possession of the resultant antibodies (See In re Kenneth Alonso October (Fed. Cir. 2008) sustaining a lack of adequate written description rejection where “the specification teaches nothing about the structure, epitope characterization, binding affinity, specificity, or pharmacological properties common to the large family of antibodies” where the specification does not characterize the antigens to which the monoclonal antibodies must bind).
The encompassed polynucleotides of the claims are broad in scope and there is substantial variation within the genus based on the teachings in the specification.
State of the Relevant Art
By the time the invention was made, it was also well-established in the art that the formation of an intact antigen-binding surface on an antibody required the association of the complete heavy and light chain variable regions, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Franssen, Frontiers in Bioscience, 13:1619-33 (2008) (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While this overall architecture is shared among 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, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (PTO-892); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (PTO-892), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. 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. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
The specification fully discloses a limited example of an anti-CD3 (epsilon) dsFv comprising the sequences
[0067] In some of any of the provided embodiments, the anti-CD3 antibody or antigen-binding fragment comprises a VH CDR1 comprising the amino acid sequence TYAMN (SEQ ID NO: 16); a VH CD2 comprising the amino acid sequence RIRSKYNNYATYYADSVKD (SEQ ID NO: 17); a VH CDR3 comprising the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO: 18), a VL CDR1 comprising the amino acid sequence RSSTGAVTTSNYAN (SEQ ID NO: 19); a VL CDR2 comprising the amino acid sequence GTNKRAP (SEQ ID NO: 20); and a VL CDR3 comprising the amino acid sequence ALWYSNLWV (SEQ ID NO: 21).
[0068] In some embodiments, the anti-CD3 dsFv comprises: a VH having the amino acid sequence of any of SEQ ID NOS: 14, 44, and 32-62 or a sequence that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of SEQ ID NOS: 14, 44, and 32-62; and a VL having the amino acid sequence of any of SEQ ID NOS: 15, 72, and 63-81 or a sequence that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of SEQ ID NOS: 14, 44, and 32-62. In some cases, the anti-CD3 dsFv comprises the amino acid sequence of SEQ ID NO: 14 and the amino acid sequence of SEQ ID NO: 15. In some cases, the anti-CD3 dsFv comprises the amino acid sequence of SEQ ID NO: 44 and the amino acid sequence of SEQ ID NO: 72.
The specification fully discloses limited examples of single variable domain antigen binding domains. The working examples in the specification of a multispecific polypeptide construct comprising an antigen binding domain comprising a single VH or VL (dAb) and which retains the full antigen binding properties in the construct format for a TAA are shown for FRalpha and cMet. The specification teaches sequences for dAbs against those TAA as follows:
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FIGS. 18 and 19A-19D show constructs targeting Folate Receptor (FRa); FIG. 20A-20D shows constructs targeting cMET.
Are the disclosed antibody species representative of the claimed genus?
It is asserted that the disclosed species are not representative of the claimed genus for any anti-CD3 and any anti-TAA antibodies much less that retain their specific binding ability within the heterodimeric Fc region complex.
The genus of all possible anti-CD3 antibodies encompassed by the claimed anti-CD3 dsFv could be structurally distinct but unpredictable whether the structure/function correlation was met for binding to CD3. The disclosed species include examples discussed herein above. Yet the specification does not identify which CDRs, which combination of fewer than all six CDRs, or which subset of residues in the combination of CDRs is essential for the recited function of binding CD3. Neither the specification nor the prior art provides guidance as to what structural changes can be made to the parent sequences and still predictably arrive at an antibody that binds CD3. The disclosed species therefore do not represent the claimed genus.
The genus of just any anti-TAA antibody is infinite in scope and for the same reasons and rationale set forth herein above for the genus of anti-CD3 antibodies. The disclosed species therefore do not represent the claimed genus.
See claim 1 from parent patent 11866507 (PTO 892) for allowable subject matter that falls within the scope of this and the corresponding specification.
Has Applicant provided a common structure sufficient to visualize the genus?
As recently as 2020, researchers were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Even though the protein sequence of CD3 or the species of TAA in claim 10 was known in the art, this would not have translated into knowledge of the genus of antibodies that could possibly engage it. Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the multispecific polypeptide constructs for reliably assigning different antibody binding structures based on the limited data shown in the application, which would support the premise that the inventors possessed the full scope of the claimed invention.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
9. Claims 1-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dixit et al. (US 20140072581; filed 7/23/2013).
The interpretation of the claims is discussed above and throughout under the BRI standard. Notably, the rejected claims do not describe the CD3 dsFv fragment as to whether the VH and VL are connected by an interdomain disulfide bond or in which the VH and VL are connected by a linker as well as an interchain disulfide bond. The proviso is that they are connected to one of each of the Fc polypeptides without an apparent physical aspect connecting the VH or VL.
The claimed polynucleotide encoding a multispecific polypeptide construct is prima facie obvious over Dixit.
Dixit teaches a bispecific binding structure that most similarly encompasses instant claims 1-2, 10 and 15-16:
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, where the construct comprises heterodimeric Fc polypeptides having mutations that promote the formation of stability for the Fc pair [0044] such as knob into hole mutations at [00254]; where the VH and VL are linked to opposite polypeptides of the heterodimeric Fc, where the construct binds CD3 [0015], where at least one other antigen binding domain formatting a multispecific construct [0106] is present for a TTA e.g., HER2 [0015] (claim 10) encoded by polynucleotides at [0079].
As regards Claims 2-3, Dixit teaches tandem nucleic acid sequences at
[0047] Provided is a method of engineering features in the Fab portion of the antibody so as to facilitate selective pairing of the obligate light and heavy chain domains. The successive expression of the obligate domains in a serial manner provides a kinetically favorable opportunity for the neighboring domains to interact and pair up preferentially.
As regards Claim 4, Dixit teaches cleavable proteins at
[0180] Furthermore, different host cells have characteristics and specific mechanisms for the translational and post-translational processing and modification (e.g., phosphorylation, cleavage) of proteins. Appropriate cell lines can be chosen to ensure the desired modifications and processing of the foreign protein expressed.
[0188] Provided are immunoglobulin constructs which are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH.sub.4; acetylation, formylation, oxidation, reduction; metabolic synthesis in the presence of tunicamycin; etc.
AS regards claim 5, Dixit teaches a shared a promoter at
[0183] In addition, techniques known in the art may be used to operably associate heterologous polynucleotides and/or heterologous control regions (e.g., promoter and/or enhancer) with endogenous polynucleotide sequences encoding a Therapeutic protein via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication Number WO 96/29411; International Publication Number WO 94/12650; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of each of which are incorporated by reference in their entireties).
AS regards claim 6, Dixit teaches the two polypeptides are expressed by different vectors at
[0116] Provided herein are host cells comprising nucleic acid encoding an immunoglobulin construct described herein. In certain embodiments, the nucleic acid encoding the first monomeric protein and the nucleic acid encoding the second monomeric protein are present in a single vector. In certain embodiments, the nucleic acid encoding the first monomeric protein and the nucleic acid encoding the second monomeric protein are present in separate vectors.
As regards claim 7, Dixit teaches and as depicted in Figure 5, the TAA antigen binding domain is amino-terminal to the Fc polypeptide.
AS regards claim 8, Dixit teaches and as depicted in Figure 5, the construct may comprise two antigen binding domains.
AS regards claim 9, Dixit teaches and as depicted in Figure 5, the antigen binding domain may be amino terminal to or carboxy terminal to the CD3 binding region.
AS regards claims 11 and 17, Dixit teaches and as depicted in Figure 5, where two antigen binding domains bind the same antigen.
AS regards claim 12 and 18, Dixit teaches where the first and second antigen binding domains bind different antigens at [0202; 0225].
AS regards claim 13 and 19-22, Dixit teaches and as depicted in Figure 5, the structure for the antigen binding domains comprising a single domain heavy chain and single domain light chain antibody.
AS regards claims 23-30, Dixit teaches vector and host cells for expressing the multispecific polypeptide constructs at
[0116] Provided herein are host cells comprising nucleic acid encoding an immunoglobulin construct described herein. In certain embodiments, the nucleic acid encoding the first monomeric protein and the nucleic acid encoding the second monomeric protein are present in a single vector. In certain embodiments, the nucleic acid encoding the first monomeric protein and the nucleic acid encoding the second monomeric protein are present in separate vectors.
[0020] In an embodiment is a process for the production of a pharmaceutical composition described herein, said process comprising: culturing a host cell under conditions allowing the expression of an immunoglobulin construct as described herein; recovering the produced immunoglobulin construct from the culture; and producing the pharmaceutical composition.
AS regards claims 31-34, Dixit teaches methods for using host cells for expressing the multispecific polypeptide constructs at
[0154] In certain embodiments is a method of producing an expression product containing a an immunoglobulin construct described herein, in stable mammalian cells, the method comprising: transfecting at least one mammalian cell with: at least one DNA sequence encoding said immunoglobulin construct to generate stable mammalian cells; culturing said stable mammalian cells to produce said expression product comprising said immunoglobulin construct. In certain embodiments, the mammalian cell is selected from the group consisting of a VERO, HeLa, HEK, NS0, Chinese Hamster Ovary (CHO), W138, BHK, COS-7, Caco-2 and MDCK cell, and subclasses and variants thereof.
The polynucleotides described in Dixit comprise multispecific polypeptides which when combined with appropriate constant domain polypeptides allow the formation of correctly paired antibody structures. The de minimus structure shown in Figure 5 of Dixit demonstrates that at least the most generic claims of the present invention are taught by Dixit based on the breadth and scope of the instant claims. Accordingly, where the technology is taught and enabled by the prior art, the ordinary artisan would have been motivated and reasonably assured of success in having produced and expressed the instant claimed polypeptides having the selective assembly of an asymmetric multispecific IgG-like antibody, thus eliminating the problem of selective pairing of the light and heavy chain, and which has been a difficult problem to address because a total of four possible pairings of heavy and light chains. See [0045] of the instant specification.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
10. Claims 1-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 12195533. The ref patent claims are not afforded safe harbor under 35 USC 121 because they share no continuity nor restriction/ speciation with the instant claims.
Although the claims at issue are not identical, they are not patentably distinct from each other because each of the claimed polypeptide/polynucleotides comprising multispecific polypeptides which when combined with appropriate constant domain polypeptides allow the formation of correctly paired antibody structures. At least the most generic claims of the invention are claimed in 12195533 based on the breadth and scope of the instant claims. Accordingly, where the technology is taught and enabled by the reference patent, the ordinary artisan would have been motivated and reasonably assured of success in having produced and expressed the instant claimed polypeptides having the selective assembly of an asymmetric multispecific IgG-like antibody, thus eliminating the problem of selective pairing of the light and heavy chain, and which has been a difficult problem to address because a total of four possible pairings of heavy and light chains.
The ref patent renders obvious the instant claims in breadth and scope for structures according to the depiction set forth as
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and comprising the disulfide-stabilized anti-CD3 binding dsFv frgment and a TAA antigen binding domain constructed within a heterodimeric Fc region comprising two different polypeptides.
11. Claims 1-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of copending Application No. 18/969,101 (reference application US 20250092137). The ref claims are not afforded safe harbor under 35 USC 121 because they share no continuity or restriction/ speciation with the instant claims.
Although the claims at issue are not identical, they are not patentably distinct from each other because each of the claimed polypeptide/polynucleotides comprising multispecific polypeptides which when combined with appropriate constant domain polypeptides allow the formation of correctly paired antibody structures. At least the most generic claims of the invention are claimed in 18/969,101 based on the breadth and scope of the instant claims. Accordingly, where the technology is taught and enabled by the reference, the ordinary artisan would have been motivated and reasonably assured of success in having produced and expressed the instant claimed polypeptides having the selective assembly of an asymmetric multispecific IgG-like antibody, thus eliminating the problem of selective pairing of the light and heavy chain, and which has been a difficult problem to address because a total of four possible pairings of heavy and light chains.
The ref renders obvious the instant claims in breadth and scope for structures according to the depiction set forth as
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and comprising the disulfide-stabilized anti-CD3 binding dsFv frgment and a TAA antigen binding domain constructed within a heterodimeric Fc region comprising two different polypeptides.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
12. Claims 1-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12331132. The ref patent claims are not afforded safe harbor under 35 USC 121 because they share no continuity nor restriction/ speciation with the instant claims.
Although the claims at issue are not identical, they are not patentably distinct from each other because each of the claimed polypeptide/polynucleotides comprising multispecific polypeptides which when combined with appropriate constant domain polypeptides allow the formation of correctly paired antibody structures. At least the most generic claims of the invention are claimed in 12331132 based on the breadth and scope of the instant claims. Accordingly, where the technology is taught and enabled by the reference patent, the ordinary artisan would have been motivated and reasonably assured of success in having produced and expressed the instant claimed polypeptides having the selective assembly of an asymmetric multispecific IgG-like antibody, thus eliminating the problem of selective pairing of the light and heavy chain, and which has been a difficult problem to address because a total of four possible pairings of heavy and light chains.
The ref patent renders obvious the instant claims in breadth and scope for structures according to the depiction set forth as
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and comprising the disulfide-stabilized anti-CD3 binding dsFv frgment and a TAA antigen binding domain constructed within a heterodimeric Fc region comprising two different polypeptides.
13. Claims 1-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 19/205,916 (reference application US 20250361319). The ref claims are not afforded safe harbor under 35 USC 121 because they share no continuity or restriction/ speciation with the instant claims.
Although the claims at issue are not identical, they are not patentably distinct from each other because each of the claimed polypeptide/polynucleotides comprising multispecific polypeptides which when combined with appropriate constant domain polypeptides allow the formation of correctly paired antibody structures. At least the most generic claims of the invention are claimed in 19/205,916 based on the breadth and scope of the instant claims. Accordingly, where the technology is taught and enabled by the reference, the ordinary artisan would have been motivated and reasonably assured of success in having produced and expressed the instant claimed polypeptides having the selective assembly of an asymmetric multispecific IgG-like antibody, thus eliminating the problem of selective pairing of the light and heavy chain, and which has been a difficult problem to address because a total of four possible pairings of heavy and light chains.
The ref renders obvious the instant claims in breadth and scope for structures according to the depiction set forth as
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403
796
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and comprising the disulfide-stabilized anti-CD3 binding dsFv frgment and a TAA antigen binding domain constructed within a heterodimeric Fc region comprising two different polypeptides.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
14. No claims are allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached on Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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