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 Group I, claims 7, 8, 17, 18, 28, 32-34, 39-49, 52, and 66, and the required species in the reply filed on 1/20/2026 is acknowledged. Applicant also canceled claims 15, 16, 29, and 129.
Applicant elected the following species:
A first polypeptide having the structure of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc, and
A second polypeptide having the structure of: VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc.
Claims 73-76 and 84-85 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 17 and 18 are withdrawn from consideration as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/20/2026.
Amended claims 7, 8, 28, 32-34, 39-49, 52, and 66 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 12/21/2023, 9/11/2024, and 1/20/2026 are in compliance with 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
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.
Scope of Enablement
Claims 7, 8, 28, 32-34, 39-48, 52, and 66 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 antigen binding polypeptide complexes wherein each binding domain comprises an immunoglobulin light chain variable region and an immunoglobulin heavy chain variable region that form an antigen binding pair and specifically bind to a SARS-CoV-2 protein, does not reasonably provide enablement for similar complexes containing any single variable domains such as immunoglobulin light chain variable regions or heavy chain variable regions that specifically bind to a SARS-CoV-2 protein independently of forming an antigen binding pair with its complementary variable region. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The breadth of the claims is found in claim 7.
The nature of the invention is an antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide has a structure represented by: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; the second polypeptide has a structure represented by: VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; and wherein VL1, VL2, VL3, and VL4 are first, second, third, and fourth Ig light chain variable regions that specifically bind to a SARS-CoV-2 protein, and VH1, VH2, VH3, and VH4 are first, second, third, and fourth Ig heavy chain domains that specifically bind to a SARS-CoV-2 protein.
The level of skill of one skilled in this art is high.
The specification teaches a number of multispecific antibodies, but does not appear to disclose a VL1, VH1, VL2, VH2, VL3, VH3, VL4, or VH4 immunoglobulin domain that is capable of binding to a SARS-CoV-2 antigen without the presence of its cognate heavy or light immunoglobulin domain.
These teachings do not enable the full breadth of the claims because an antibody lacking all parental CDRs would not predictably bind antigen. Notably, the instant claims indicate that the VL1, VL2, VL3, VL4, VH1, VH2, VH3, and VH4 are each regions that specifically binds to a SARS-CoV-2 protein (claim 7).
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). 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 (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody binding domain comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of an antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antigen binding polypeptide domains as broadly as currently claimed.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Paul and Bendig, the lack of guidance and direction provided by applicants, and the absence of working examples, undue experimentation would be required to make and use functional antibodies with binding domains having fewer than all six CDRs with a reasonable expectation of success, absent a specific and detailed description in applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Written Description
Claims 7, 8, 28, 32-34, 39-48, 52, and 66 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.
The instant claims above are drawn to a genus of antigen binding polypeptide complexes comprising a first polypeptide and a second polypeptide, wherein each polypeptide has a number of immunoglobulin light chain variable regions and heavy chain variable regions that each specifically bind to a SARS-CoV-2 protein, defined only by the configuration of immunoglobulin variable regions, Fc, and linkers within the polypeptides. They are not defined by any structure other than being generically antibody as defined by the specification. Yet, the specification provides no such immunoglobulin heavy chain or light chain variable region structures that specifically binds to a SARS-CoV-2 protein in-and-of-itself, in the absence of a corresponding light or heavy chain variable region. When one goes to the instant specification to identify a representative number of species to define the claimed genera with respect to immunoglobulin light chain variable regions or heavy chain variable regions that alone specifically bind to a SARS-CoV-2 protein, they do not find any representative species of a single immunoglobulin variable domain that has been shown to bind a SARS-CoV-2 protein. Even if the prior art is aware of additional antibodies, the totality of known antibodies would not be representative of each entire genus for the reasons discussed below.
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
“[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.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus antibody with specific epitope, Applicant must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. . A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the antibodies claimed can have any CDR set, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” One of skill in this art cannot envision the structure of any immunoglobulin light chain variable regions or heavy chain variable regions that alone specifically bind to a SARS-CoV-2 protein. Therefore, since only a single species is provided to represent these genera, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim 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).
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since the CDR set of each antibody is responsible for antigen binding function of an antibody, and said set varies structurally from antibody to antibody, there is no correlation between structure and function between the members of an antibody genus. One cannot “represent” the entire genus defined only by function with any structural consensus. Thus, functional language should not be used to define an antibody genus. Rather, structure should be used.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. Four species is certainly not adequate.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
Since no VL or VH are taught within the claimed genera above, those that bind a SARS-CoV-2 protein, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe these genera. Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of immunoglobulin light chain variable regions or heavy chain variable regions that alone specifically bind to a SARS-CoV-2 protein of claim 7, broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Owed to the variation among antibodies with respect to their CDRs, the structure of antibodies that correlates with their function, it is very difficult to provide adequate representation of a functionally defined antibody genus. There is unlikely to be any CDR structure shared by the entire genus, for example. Also, the disclosure of one set of antibody CDRs does not guide one of skill to the next set of CDRs. This is because it is well-known in this art that mutation of CDR residues leads to loss of antigen binding. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Thus, while applicant has described one or a few species within each of the genera recited, and the art may provide more, each genus is very large and would encompass antibody structures (CDR sets) that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the antibody structures encompassed by the claimed genera only defined by function. Any future antibody structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of antibodies. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite that an immunoglobulin light chain variable region in complex with an immunoglobulin heavy chain variable region specifically binds to a SARS-CoV-2 protein (i.e., VL1 in complex with VH1 and so forth).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28, 39, and 46 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 28 and 39 recite “about 50 amino acids” and “about 10 µM to about 1 pM” on lines 2 and 3, respectively. The specification indicates
"about" refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, about" can mean within 1 or more than 1 standard deviation per the practice in the art. Alternatively, "about" can mean a range of up to 10% or 20% (i.e., +10% or ±20%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 5-fold of a value. When particular values or compositions are provided in the application and claims, unless otherwise stated, the meaning of "about" should be assumed to be within an acceptable error range for that particular value or composition.
(para. 263)
However, that definition is inadequate to clearly define the metes and bounds of the term “about” as used in the claims, since the definition is a number of examples, instead of clear requirements. Further, “acceptable”, which is used in the definition, is a relative term.
Regarding claim 46, it requires the antigen binding fragment to be a Fab, scFab, Fab’, F(ab’)2, Fv, or scFv. However, the antigen binding complex of claims 7 and 43, from which claim 46 depends, possess substantially more domains that is possible in such binding fragments. The metes and bounds of claim 46 are unclear because it is not clear if each binding domain should be a Fab, scFab, Fab’, F(ab’)2, Fv, or scFv, or the claim is intended to mean that the entire antigen binding fragment is a Fab, scFab, Fab’, F(ab’)2, Fv, or scFv.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 28, 43, and 46 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 28 recites the limitation “wherein linkers L1-L16 each independently have a length of from 0 amino acids to about 50 amino acids” on lines 2-3, and claim 28 depends from claim 7, which recites “L1-L16 are amino acid linkers” on line 34. However, claim 7 requires an amino acid linker, and yet claim 28 indicates that the linker can be 0 amino acids in length—meaning, there is no amino acid linker.
Claim 43 recites the limitation “an antibody or antigen binding fragment thereof”, however, claim 7 is already an antibody or antigen binding fragment thereof.
Claim 46 does not further limit the claims it depends from, because the antibody or antigen binding fragment thereof described in claims 43 and 7 is much larger than one fragment, however, claim 46 requires the antibody or antigen binding fragment thereof to be a single fragment.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 7-8, 28, 32, 39-49, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Alt, et al. (FEBS Letters 454, 1999, 90-94), in view of Kovacech, et al. (EBioMedicine. 2022 Feb;76:103818. doi: 10.1016/j.ebiom.2022.103818), Liu, et al. (WO 2021035096 A1, published 2/25/2021), and Choi, et al. (Mol Cancer Ther. 2013 Dec;12(12):2748-59.).
The claimed invention is represented by claim 7, which is drawn to an antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide has a structure represented by: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; wherein the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fcl; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL2 is a second immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL3 is a third immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally, an immunoglobulin hinge; and L1-L16 are amino acid linkers.
The Prior Art
Alt teaches bispecific IgG-like antibody molecules, wherein fusion of a single-chain diabody to the Fc of the human immunoglobulin γ1 chain results in the expression of dimeric fusion proteins exhibiting four functional antigen binding sites with increased functional affinity (Figs. 1 & 3-6; Abstract). For instance, scDb-Fc disclosed by Alt has the structure VHA-linker-VLB-linker-VHB-linker-VLA-linker-CH2-CH3 (of a Fc domain; Fig. 1). However, Alt does not teach an antigen binding polypeptide complex comprising a first polypeptide and second polypeptide wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-Fc and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc wherein VL1, VL2, VL3, and VL4 are first through fourth Ig light chain variable regions that specifically bind to a SARS-CoV-2 protein and VH1, VH2, VH3, and VH4 are first through fourth Ig heavy chain variable regions that specifically bind to a SARS-CoV-2 protein.
Kovacech teaches second-generation antibodies which were selected for their ability to neutralize SARS-CoV-2 variants of concern, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta; p. 1). Kovacech also discloses that human antibodies isolated from COVID-19 convalescent patients often target the RBD of the spike protein of SARS-CoV-2, and recognize distinct, sometimes non-overlapping epitopes (p. 2, col. 2, para. 1). Kovacech teaches that the majority of neutralizing antibodies against SARS-CoV-2 in clinical development were derived from convalescent patients who recovered from COVID-19, and such antibodies derived from human B cells do not require an extensive humanization process, resulting in fast-forwarded manufacture (p. 2, col. 2, para. 2). Kovacech’s method to generate fully matured antibodies with high neutralizing potency against live SARS-CoV-2 virus involved immunizing mice with recombinant S protein or RBD (p. 10, col. 1, last para.) Screening of the antibody-expressing mouse hybridoma clones generated from the S-immunized mice revealed all except one (97.6%) target the RBD of the SARS-CoV-2 S protein (Fig. 1A; clone 3). Thirteen hybridoma clone supernatants inhibited the interaction between RBD and ACE2 in a competition ELISA (Fig. 1C) and the neutralizing antibodies bind RBD with nanomolar or sub-nanomolar affinities (Fig. 1h). Notably, of the antibodies that are specific for S RBD, mutual competition assays revealed three non-overlapping antibody epitopes (Fig. 2a, epitopes I, II, and III; p. 10, col. 2, last para.). Kovacech also discloses mouse-human chimeric versions of some of their antibodies with their variable regions fused to human kappa and IgG1 constant regions (p. 14, col. 2; Fig. 6), which maintain potent neutralizing activities against SARS-CoV-2 and variants of concern (B.1, Alpha, Beta, and Delta; Fig. 6c, p.14, col. 2, paras. 4-6). Kovacech further discloses subcutaneous inoculation of monoclonal antibodies prior to infection with SARS-CoV-2 (Fig. 7). Additionally, Kovacech demonstrates that combination of antibodies with non-overlapping epitopes prevents rapid mutational escape of authentic SARS-CoV-2 virus, whereas individual antibodies were susceptible to escape (Fig. 5, p. 12, col. 2;p. 14, col. 1).
It would have been obvious, based on the teachings above, before the filing of the instant application to create an antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide, exhibiting four functional antigen binding sites with increased functional affinity, wherein each binding domain is specific for a SARS-CoV-2 protein.
However, neither reference above teaches variable regions in the orientation VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc.
This deficiency is remedied by the art below.
Liu teaches polypeptides comprising an antigen binding unit directed to a cellular target bound by an exogenous molecule for a range of purposes including therapeutics, diagnostics, and research tools (Abstract). Liu further discloses a bivalent antigen binding unit that comprises two scFVs, a bispecific scFv, and each scFV may comprise one VH and one VL region; further, the bivalent scFv may be a tandem bi-scFv or a diabody comprising four domains in a single linear polypeptide: VH1 and VL1 of a first antigen binding unit and VH2 and VL2 of a second antigen binding unit, which may be arranged in different formats, including VL1-Lx-VL2-Ly-VH2-Lz-VH1, where Lx, Ly, and Lz are linkers that may be the same or different (para. [00150]). Liu also discloses that linkers may be peptide linkers of any length, for example, from 1 amino acid to 20 amino acids long (para. [00152]).
Choi discloses that heterodimeric Fc designed by engineering the CH3 homodimeric interface of immunoglobulin G1 serves as an attractive scaffold for the generation of bispecific antibodies (bsAb) due to the favorable properties of the Fc region (Abstract). Choi specifically describes the bsAb bsVeMet, which consists of two scFv arms with different binding specificities, fused to the N-terminus of a heterodimeric Fc (Fig. 4A; p. 2753). Notably, bsVeMet exhibited more potent antitumor efficacy than both the parent monospecific antibodies alone (Abstract; Figs. 5-6). Choi also discloses that a pioneering breakthrough in the development of heterodimeric Fcs, “knobs-into-holes” (KiH), are asymmetric hydrophobic mutations introduced between the homodimeric CH3 domains at their interface in human IgG1, i.e., a “knob” mutation into one CH3 domain and “hole” mutations introduced into the other CH3 domain (p. 2748, col. 2).
It would have been obvious to one of ordinary skill in the art to modify the dimeric fusion proteins exhibiting four functional antigen binding sites disclosed by Alt to incorporate the variable domains of the anti-SARS-CoV-2 spike antibodies disclosed by Kovacech with non-overlapping epitopes. It would have been further obvious to configure the variable regions in the orientation VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc, because, because Liu discloses the VL1-Linker-VL2-Linker-VH2-Linker-VH1 configuration for diabodies comprising four domains in a single linear polypeptide. Thus, a reasonable expectation of success would have been enjoyed by a PHOSITA before filing using this design. Along those lines, it would have been obvious to configure the second polypeptide to have the structure VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc. This is the same design as above but using different antibody domains and Choi teaches that bispecific antibodies can consist of two arms with different binding specificities fused to Fc. Regarding linker lengths, a length from 1 amino acid to about 50 amino acids would have been obvious, since Liu discloses peptide linkers may be of any length, such as 1 amino acid to 20 amino acids long. One of ordinary skill in the art would have been motivated to have a stable, high avidity binding molecule that can target four SARS-CoV-2 antigens. For instance, Kovacech discloses many suitable SARS-CoV-2 antibodies, the VL and VH domains of which could be incorporated into a multivalent molecule, such as VL and VH domains from an antibody that binds each of the three RBD non-overlapping epitopes, as well as VL and VH domains from the antibody that binds elsewhere on the spike protein. It is well known that the spike protein of SARS-CoV-2 is a trimer and so the three antibodies of Kovacech above are sufficient to make the obvious molecule function with anyone of the antibodies simply being used twice in the design, adding predictably to overall avidity.
The binding complex rendered obvious by the cited references would inherently be trispecific, or tetraspecific, and have a greater neutralization potency against SARS-CoV-2 virus than a monospecific antigen binding polypeptide complex or a mixture of monospecific antigen binding polypeptide complexes that specifically bind to the same antigens as the bispecific, trispecific, or tetraspecific antigen binding polypeptide complex, because the trivalent/trispecific configuration would have increased avidity. That is also the case for when the SARS-CoV-2 virus is one of the strains or variants of concern Kovacech demonstrates specific binding to and neutralization of. Additionally, the binding complexes rendered obvious by the cited references would inherently exhibit improved prevention of immune escape compared to (i) a monovalent anti-SARS-CoV-2 antibody that binds to one of the same antigens as the anti-SARS-CoV-2 multivalent antibody, and/or (ii) a combination of monovalent anti-SARS-CoV-2 antibodies that binds to the same antigens as the anti-SARS-CoV-2 multivalent antibody, because the multivalent antibody would have increased avidity and also Kovacech demonstrates that although the disclosed antibodies generally prevent immune escape, some mutations may lead to immune escape against particular antibodies, but escape was not observed in antibody combinations with non-overlapping epitopes, so one would expect that a multivalent antibody with specificity for three or four distinct epitopes would be less likely to be susceptible to immune escape than a monovalent antibody that is specific for only one epitope.
An antibody or antigen binding fragment thereof comprising the antigen binding polypeptide complex, or more specifically wherein the antibody is IgG or IgG1 would also be obvious because the cited references disclose IgG and IgG1 antibodies and domains. Similarly, the cited references teach antibody or antigen-binding fragments that are scFvs, and antibodies that are monoclonals or humanized and mouse-human chimeras. Furthermore, a pharmaceutical composition comprising the antigen binding polypeptide complex and a pharmaceutically acceptable carrier would be obvious because Kovacech discloses subcutaneous inoculation of mice with mAbs, which would inherently possess a pharmaceutically acceptable carrier.
It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Since Applicant has not disclosed that the specific limitations recited in instant claims are for any particular purpose or solve any stated problem, and the prior art teaches that parameter magnitudes that are encompassed by instant claims, often vary according to the sample being analyzed and various matrices, solutions and parameters appear to work equally as well, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the art. With respect to claim 39, it would have been obvious to optimize affinity of the multispecific molecule made obvious above to be as low as possible to improve functionality. The nanomolar affinity for each antibody of Kovacech would satisfy the functional language of this claim also as the apparent affinity would be even lower once each binding domain with nanomolar affinity is combined into one complex as discussed supra.
With respect to claim 44-45, it would have been obvious to use human IgG1 isotype for the Fc region as was done in the design of Alt as it would provide a reasonable expectation of success as a dimerization domain to make the obvious antibody.
With respect to claim 47, Kovacech teaches chimeric antibody generation and that humanization is known for antibodies and to a PHOSITA, this would have made more than obvious humanization of the chimeric binding domains of Kovacech for use in a therapeutic multivalent antibody like the one made obvious here so as to avoid the well-known HAMA response, which would hurt therapeutic efficacy over time in each patient. With respect to claim 48, the obvious multivalent antibody is considered monoclonal in that all molecules in a solution thereof would be the same, generated recombinantly. Furthermore, humanized antibodies are CDR-grafted.
With respect to 46, the obvious molecule here contains Fv fragments, though it clearly cannot be just an Fv fragment.
There would be a reasonable expectation of success because there is a high level of skill in the art and similar binding configurations are well known in the art. Therefore, claims 7-8, 28, 32, 39-49, & 52 were prima facie obvious before the priority date of the instant invention.
Claims 33 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Alt, Kovacech, Liu, and Choi (supra) as applied to claims 7-8, 28, 32, 39-49, & 52 above, and further in view of Ying, et al. (PGPub US20220185875A1, published 6/16/2022, priority date 3/18/2019).
The claimed invention encompasses particular knob-into-hole mutations (claims 33-34) and a kit comprising the antigen binding complex (claim 66).
The Prior Art
The teachings of Alt, Kovacech, Liu, and Choi are described above. However, they do not teach knob-into-hole modification that comprises knob substitutions of S354C and T366W and hole substitutions of Y349C, T366S, L368A, and Y407V based on the EU numbering scheme.
Ying discloses bispecific antibodies (Abstract). Ying also teaches a kit comprising an anti-ANG2 single domain antibody or bispecific antibody (para. [0073]). Further, Ying discloses an IgG1-IgG4 heavy chain constant region variants with site-directed modifications and knob-into-hole mutations (para. [0111]). Ying also discloses the specific knob mutations T366W and S354C and hole mutations T366S, L368A, Y407V, and Y349C (para. [0126]).
It would have been obvious to one of ordinary skill in the art to modify the teachings of Alt, Kovacech, Liu, and Choi to incorporate specific Fc mutations taught by Ying. Ying discloses suitable knob-into-hole mutations (knob mutations T366W and S354C and hole mutations T366S, L368A, Y407V, and Y349C). Choi already discloses the utility of knob-into-hole mutations for purposes such as Fc heterodimer formation. One of ordinary skill in the art would have been motivated to make antigen-binding complexes with heterodimeric Fc regions. There would be a reasonable expectation of success because the prior art recognized the effects of these mutations. Further, it would have been obvious to one of ordinary skill in the art to make a kit comprising the antigen binding polypeptide complexes rendered obvious by the prior art, because Ying discloses kits comprising different types of antibodies, including bispecific antibodies. Therefore, claims 33 and 66 were prima facie obvious before the priority date of the instant invention.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Alt, Kovacech, Liu, and Choi (supra), as applied to claims 7-8, 28, 32, 39-49, & 52 above, and further in view of Wang (Immunotargets Ther. 2022 May 18;11:23-35. doi: 10.2147/ITT.S360151) and Saunders (Front Immunol. 2019 Jun 7;10:1296. doi: 10.3389/fimmu.2019.01296. PMID: 31231397).
The claimed invention encompasses the antigen binding polypeptide complex that is an IgG1 or IgG4 antibody and the effector function knockout mutation is L234A, L235A, P239A or a combination thereof, based on the EU numbering scheme (claim 34).
The Prior Art
The teachings of Alt, Kovacech, Liu, and Choi are described above. However, they do not provide a reason for why Fc effector function mutations may benefit antiviral antibodies.
Wang discloses that cytokine release syndrome (CRS) is triggered by SARS-CoV-2 infections, and discusses various strategies for managing CRS triggered by SARS-CoV-2 (Abstract). Wang further teaches that CRS is an excessive or uncontrolled release of proinflammatory cytokines and is potentially linked to the deadly coronavirus infection (p.26, para. 3). Consequences of COVID-19 triggered CRS include serious organ damage (cardiovascular, liver, neurologic manifestations, and renal injuries) that result in organ failure and death, and severe pulmonary inflammation causes damage to pulmonary vasculature and may trigger pulmonary thrombosis early in the disease course (Id.).
Saunders discloses engineering of antibody Fc for the ablation of effector functions, which can be beneficial in certain situations (p. 11, col. 1, paras. 1-2). Saunders further describes antibody induced proinflammatory cytokine secretion, which results in toxicity, may be alleviated by Fc region of the antibody being mutated to eliminate FcγR, and the combination of Leu234Ala and Leu235Ala (commonly called LALA mutations), eliminated detectable binding to FcγRI, IIa, and IIIa for both IgG1 and IgG4, and the use of LALA appears to be more effective than either Leu234Ala or Leu235Ala alone (p. 11, col. 1, para. 3).
It would have been obvious to one of ordinary skill in the art to modify the teachings of Alt, Kovacech, Liu, and Choi, to incorporate specific Fc mutations (L234A and L235A) taught by Saunders for the purpose of eliminating FcγR binding to alleviate proinflammatory cytokine secretion. One of ordinary skill in the art would be motivated to do so because Wang discloses that cytokine release syndrome is triggered by SARS-CoV-2 infections and can result in serious organ damage, organ failure, and death. At the very least, because antibodies can be associated with proinflammatory cytokine release, and cytokines are associated with severe disease in SARS-CoV-2 infection, one of skill in the art would at the very least want to limit further pro-inflammatory cytokine release, and LALA mutations to Fc can prevent antibody-associated cytokine release. There would be a reasonable expectation of success because the prior art recognized the effects of these mutations Therefore, claim 34 was prima facie obvious before the priority date of the instant invention.
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 7-8, 28, 32-34, 39-49, 52, and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 128-142,147, and 148 of copending Application No. 17/936,041 (PGPub US20230203199A1) in view of Kovacech, et al. (EBioMedicine. 2022 Feb;76:103818. doi: 10.1016/j.ebiom.2022.103818), Liu, et al. (WO 2021035096 A1, published 2/25/2021), Ying, et al. (PGPub US20220185875A1, published 6/16/2022, priority date 3/18/2019), Wang (Immunotargets Ther. 2022 May 18;11:23-35. doi: 10.2147/ITT.S360151), and Saunders (Front Immunol. 2019 Jun 7;10:1296. doi: 10.3389/fimmu.2019.01296. PMID: 31231397).
Each set of claims encompasses an antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first and second polypeptides have similar structure: VL1-L1-VL2-L2-VH2-L3-VH1-Fc and VL3-L5-VL4-L6-VH4-L7-VH3-Fc, respectively. The difference in the claim sets is that the copending application is more generic regarding the specificity of the VL and VH chains, whereas the instant application requires VLs and VHs that specifically bind a SARS-CoV-2 antigen. Additionally, each set of claims encompasses the Fc region comprising knob-into-hole modifications, an antibody or antigen binding fragment thereof comprising the antigen binding polypeptide complex, the antigen binding fragment is a Fab, scFab, Fab’, F(ab’)2, Fv, or scFv, wherein the antibody is human or humanized, or a pharmaceutical composition comprising the antigen binding polypeptide complex and a pharmaceutically acceptable carrier.
The copending claims do not specifically encompass linkers having a length between 0 and 50 amino acids, the specific knob-into-hole or Fc effector function knockout mutation, a kit comprising an antibody or antigen-binding complex, or wherein the VL1-VL4 and VH1-VH4 regions specifically bind to SARS-CoV-2 protein, but that would be obvious to one of ordinary skill in the art in view of Kovacech, Liu, and Ying.
Kovacech teaches second-generation antibodies which were selected for their ability to neutralize SARS-CoV-2 variants of concern, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta; p. 1). Kovacech also discloses that human antibodies isolated from COVID-19 convalescent patients often target the RBD of the spike protein of SARS-CoV-2, and recognize distinct, sometimes non-overlapping epitopes (p. 2, col. 2, para. 1). Kovacech teaches that the majority of neutralizing antibodies against SARS-CoV-2 in clinical development were derived from convalescent patients who recovered from COVID-19, and such antibodies derived from human B cells do not require an extensive humanization process, resulting in fast-forwarded manufacture (p. 2, col. 2, para. 2). Kovacech’s method to generate fully matured antibodies with high neutralizing potency against live SARS-CoV-2 virus involved immunizing mice with recombinant S protein or RBD (p. 10, col. 1, last para.) Screening of the antibody-expressing mouse hybridoma clones generated from the S-immunized mice revealed all except one (97.6%) target the RBD of the SARS-CoV-2 S protein (Fig. 1A; clone 3). Thirteen hybridoma clone supernatants inhibited the interaction between RBD and ACE2 in a competition ELISA (Fig. 1C) and the neutralizing antibodies bind RBD with nanomolar or sub-nanomolar affinities (Fig. 1h). Notably, of the antibodies that are specific for S RBD, mutual competition assays revealed three non-overlapping antibody epitopes (Fig. 2a, epitopes I, II, and III; p. 10, col. 2, last para.). Kovacech also discloses mouse-human chimeric versions of some of their antibodies with their variable regions fused to human kappa and IgG1 constant regions (p. 14, col. 2; Fig. 6), which maintain potent neutralizing activities against SARS-CoV-2 and variants of concern (B.1, Alpha, Beta, and Delta; Fig. 6c, p.14, col. 2, paras. 4-6). Kovacech further discloses subcutaneous inoculation of monoclonal antibodies prior to infection with SARS-CoV-2 (Fig. 7).
Liu teaches polypeptides comprising an antigen binding unit directed to a cellular target bound by an exogenous molecule for a range of purposes including therapeutics, diagnostics, and research tools (Abstract). Liu further discloses a bivalent antigen binding unit that comprises two scFVs, a bispecific scFv, and each scFV may comprise one VH and one VL region; further, the bivalent scFv may be a tandem bi-scFv or a diabody comprising four domains in a single linear polypeptide: VH1 and VL1 of a first antigen binding unit and VH2 and VL2 of a second antigen binding unit, which may be arranged in different formats, including VL1-Lx-VL2-Ly-VH2-Lz-VH1, where Lx, Ly, and Lz are linkers that may be the same or different (para. [00150]). Liu also discloses that linkers may be peptide linkers of any length, for example, from 1 amino acid to 20 amino acids long (para. [00152]).
Ying discloses bispecific antibodies (Abstract). Ying also teaches a kit comprising an anti-ANG2 single domain antibody or bispecific antibody (para. [0073]). Ying discloses an IgG1-IgG4 heavy chain constant region variants with site-directed modifications and amino acid substitutions in the heavy constant regions, including L234A, L235A, or S228P mutations, or knob-into-hole mutations (para. [0111]). Ying also discloses the specific knob mutations T366W and S354C and hole mutations T366S, L368A, Y407V, and Y349C (para. [0126]). As discussed in the rejection under 35 U.S.C. §103 above, Wang and Saunders disclose that SARS-CoV-2 is associated with harmful cytokine release and that Fc mutations that prevent FcγR binding can alleviate release of proinflammatory cytokines, respectively.
The instant claims would have been obvious to one of ordinary skill in the art when combined with the teachings of Kovacech, Liu, and Ying, Wang and Saunders. One of ordinary skill in the art would have been motivated to make or use an antigen binding polypeptide complex with high avidity for SARS-CoV-2 proteins.
This is a provisional nonstatutory double patenting rejection.
Claims 7-8, 28, 32-34, 39-49, 52, and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 108-124 & 127-128 of copending Application No. 17/936,044 in view of Alt, et al. (FEBS Letters 454, 1999, 90-94), Kovacech, et al. (EBioMedicine. 2022 Feb;76:103818. doi: 10.1016/j.ebiom.2022.103818), Liu, et al. (WO 2021035096 A1, published 2/25/2021), Ying, et al. (PGPub US20220185875A1, published 6/16/2022, priority date 3/18/2019), Wang (Immunotargets Ther. 2022 May 18;11:23-35. doi: 10.2147/ITT.S360151), and Saunders (Front Immunol. 2019 Jun 7;10:1296. doi: 10.3389/fimmu.2019.01296. PMID: 31231397).
Each set of claims encompasses an antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptides have a similar structure: VL1-L1-VL2-L2-VH2-L3-VH1-Fc. While the instant claims require a second polypeptide with the structure VL3-L5-VL4-L6-VH4-L7-VH3-Fc, the copending claims feature a second polypeptide with only one set of VL and VH chains. Another difference in the claim sets is that the copending application is more generic regarding the specificity of the VL and VH chains, whereas the instant application requires VLs and VHs that specifically bind a SARS-CoV-2 antigen. Additionally, each set of claims encompasses the Fc region comprising knob-into-hole modifications, an antibody or antigen binding fragment thereof comprising the antigen binding polypeptide complex, the antigen binding fragment is a Fab, scFab, Fab’, F(ab’)2, Fv, or scFv, or a pharmaceutical composition comprising the antigen binding polypeptide complex and a pharmaceutically acceptable carrier.
The copending claims do not specifically encompass linkers having a length between 0 and 50 amino acids, the specific knob-into-hole or Fc effector function knockout mutation, a kit comprising an antibody or antigen-binding complex, or wherein the VL1-VL4 and VH1-VH4 regions specifically bind to SARS-CoV-2 protein, but that would be obvious to one of ordinary skill in the art in view of Alt, Kovacech, Liu, Ying, and Saunders.
Alt teaches bispecific IgG-like antibody molecules, wherein fusion of a single-chain diabody to the Fc or CH3 region of the human immunoglobulin γ1 chain results in the expression of dimeric fusion proteins exhibiting four functional antigen binding sites with increased functional affinity (Figs. 1 & 3-6; Abstract).
The teachings of Kovacech, Liu, Ying, Wang, and Saunders are described above.
The instant claims would have been obvious to one of ordinary skill in the art when combined with the teachings of Alt, Kovacech, Liu, Ying, Wang, and Saunders. Specifically, it would be obvious that the second polypeptide chain could contain an additional VL and VH domain because Alt discloses dimeric fusion proteins exhibiting four functional antigen binding sites. One of ordinary skill in the art would have been motivated to make or use an antigen binding polypeptide complex with high affinity and avidity for SARS-CoV-2 proteins.
This is a provisional nonstatutory double patenting rejection.
Claims 7-8, 28, 32-34, 39-49, 52, and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 573, 577, and 586 of copending Application No. 19/170,000 in view of Kovacech, et al. (EBioMedicine. 2022 Feb;76:103818. doi: 10.1016/j.ebiom.2022.103818), Liu, et al. (WO 2021035096 A1, published 2/25/2021), Ying, et al. (PGPub US20220185875A1, published 6/16/2022, priority date 3/18/2019), Wang (Immunotargets Ther. 2022 May 18;11:23-35. doi: 10.2147/ITT.S360151), and Saunders (Front Immunol. 2019 Jun 7;10:1296. doi: 10.3389/fimmu.2019.01296. PMID: 31231397).
Each set of claims encompasses an antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first and second polypeptides have a similar structure: VL1-L1-VL2-L2-VH2-L3-VH1-Fc and VL3-L5-VL4-L6-VH4-L7-VH3-Fc, respectively for the instant claims. The difference in structure is that the copending polypeptides have that structure with additional CH1 and/or CL at some positions between the other immunoglobulin regions. Each set of claims also encompasses the VL1-VL4 and VH1-VH4 specifically binding to a SARS-CoV-2 protein. Additionally, each set of claims encompasses, an antibody or antigen binding fragment thereof comprising the antigen binding polypeptide complex, the antigen binding fragment is a Fab, scFab, Fab’, F(ab’)2, Fv, or scFv, or a pharmaceutical composition comprising the antigen binding polypeptide complex and a pharmaceutically acceptable carrier.
The copending claims do not specifically encompass the Fc region comprising knob-into-hole modifications (e.g.,CH2 or CH3), linkers having a length between 0 and 50 amino acids, the specific knob-into-hole or Fc effector function knockout mutation, or a kit comprising an antibody or antigen-binding complex, but that would be obvious to one of ordinary skill in the art in view of Kovacech, Liu, and Ying.
The teachings of Kovacech, Liu, Ying, Wang, and Saunders are described above.
The instant claims would have been obvious to one of ordinary skill in the art when combined with the teachings of Kovacech, Liu, Ying, Wang, and Saunders. Specifically, the instant claims’ configuration of VLs, VHs, and linkers, without CH1 and CL, would be obvious due to Liu teaching that configuration. Similarly, the presence of knob-in-hole or Fc effector function mutations would be obvious because Ying discloses that their beneficial function. One of ordinary skill in the art would have been motivated to make or use an antigen binding polypeptide complex with high affinity and avidity for SARS-CoV-2 proteins.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is (571)272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671