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 .
Claim Status
Applicant’s preliminary amendments received 19APR2024 are acknowledged.
Claims 18 and 22-23 have been canceled.
Claims 1-17 and 19-21 have been amended.
Claims 1-17 and 19-21 are pending in the instant application (i.e., Claim 1 is independent).
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/KR2022/015981, filed 22OCT2022, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of REPUBLIC OF KOREA Application No. 20-2021-0142135 filed on 22OCT2021 has been received and is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 23APR2024 and 22APR2025 is/are acknowledged and the references cited therein have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c) (For example, see p 60 (G4S or (G4S)3 or (G4S)2).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Objections
Claims 10-11, 13 and 15 are objected to because of the following informalities:
Claims 10 and 15 contain a grammatical error: “an” should be inserted prior to “electrostatic…” in all claims.
Claims 11 and 13 contain a grammatical error: “a” should be inserted prior to “peptide linker” in all claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 10 recites the limitation "the first Fc domain variant and the second Fc domain variant" which is dependent on claim 8, which recites the “first Fc domain and the second Fc domain….” Therefore, there is insufficient antecedent basis for this limitation in the claim. In this instance, amending the claim to “wherein the s….” in lines 2 and 5 or something of similar nature would obviate this rejection.
Claims 11 and 13, recite the phrase "optionally," which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(h)(II). Claims 12 and 14-17 are also rejected since they depend from claims 11 or 13, but do not remedy this deficiency.
Claim 14 recites the limitation "the VH further comprises a HC CH1 region and the VL further comprises a CL region" which is dependent on claim 13, which recites several VH/VL regions directed towards the first and/or second antigen-binding domains and therefore it is unclear which regions encompass the scope of this claim. There is insufficient antecedent basis for this limitation in the claim.
Claim 15 recites the limitation "the Fc domain monomer comprises" which is dependent on claim 11, which recites the “…A, B, C, and D are monomeric polypeptide sequences of an Fc domain…” Therefore, there is insufficient antecedent basis for this limitation in the claim. In this instance, amending the claim to “wherein
Claim 17 recites the limitation "…the binding between X and Y further comprises…" which is dependent on claim 13, which recites “…X and Y pair with each other….” Therefore, there is insufficient antecedent basis for this limitation in the claim. Furthermore, claim 17 recites, “…wherein the binding between X and Y further comprises, in addition to a disulfide bond present between CH1233 and CL214 based on Kabat numbering system, i)…or iii)….” is unclear. Amending the claim to “…wherein the pairing between X and Y further comprises, a disulfide bond present between position 233 of the CH1 and position 214 of the CL based on Kabat numbering system and i)…or iiii)….” or something of similar nature would obviate this rejection. It is noted that writing out “the position of [number] of CH1, CL, VH, or VL” would provide additional clarity.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 and 19-21 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 and having support for:
“A fusion protein comprising a) an antigen-binding site and b) two Fc domains, wherein the fusion protein comprises the polypeptides of the following structural formulas (I), (II), (III), and (IV):
N'-X-(L1)n-A-C' (I);
N'-Y-(L2)m-B-C' (II);
N'-C-C' (III); and
N'-D-C' (IV)
wherein, in the structural formulas (I), (II), (III), and (IV),
N' is the N-terminus of each polypeptide,
C' is the C-terminus of each polypeptide,
- refers to a linkage,
A, B, C, and D are monomeric polypeptide sequences of an Fc domain each comprising the CH2 and CH3 regions of an immunoglobulin, wherein A and B comprise a knob variant and C and D comprise a hole variant that promotes the formation of an Fc heterodimer (heterodimeric Fc); wherein A forms a dimer with one of C or D to form the first Fc domain, and B forms a dimer with the remaining one of C or D to form the second Fc domain;
L1 and L2 are each [a] peptide linker,
n and m are each independently 0 or 1,
X is a first polypeptide sequence of the antigen-binding site, which comprises heavy chain CDR1, CDR2, and CDR3 sequences or a heavy chain variable region comprising HCDRs1-3;
Y is a second polypeptide sequence of the antigen-binding site, which comprises light chain CDR1, CDR2, and CDR3 sequences or a light chain variable region comprising LCDRs1-3;
wherein X and Y pair with each other to form the antigen-binding site that specifically binds to an antigen;
wherein the polypeptides of (I), (II), (III), and (IV) comprise the sequences selected from the group consisting of:
SEQ ID NOs: 8, 9, 7, and 7, respectively,
SEQ ID NOs: 10, 11, 7, and 7, respectively,
SEQ ID NOs: 12, 13, 7, and 7, respectively,
SEQ ID NOs: 14, 15, 7, and 7, respectively,
SEQ ID NOs: 14, 16, 7, and 7, respectively,
SEQ ID NOs: 14, 17, 7, and 7, respectively,
SEQ ID NOs: 14, 18, 7, and 7, respectively,
SEQ ID NOs: 29, 30, 7, and 7, respectively,
SEQ ID NOs: 790, 791, 789, and 789, respectively,
SEQ ID NOs: 792, 793, 789, and 789, respectively,
SEQ ID NOs: 796, 797, 789, and 789, respectively,
SEQ ID NOs: 798, 799, 789, and 789, respectively,
SEQ ID NOs: 800, 801, 789, and 789, respectively,
SEQ ID NOs: 802, 803, 789, and 789, respectively,
SEQ ID NOs: 43, 44, 42, and 42, respectively,
SEQ ID NOs: 45, 46, 42, and 42, respectively,
SEQ ID NOs: 67, 68, 7, and 7, respectively,
SEQ ID NOs: 69, 70, 7, and 7, respectively,
SEQ ID NOs: 71, 72, 7, and 7, respectively,
SEQ ID NOs: 568, 569, 7, and 7, respectively,
SEQ ID NOs: 570, 571, 7, and 7, respectively,
SEQ ID NOs: 590, 591, 7, and 7, respectively,
SEQ ID NOs: 592, 593, 7, and 7, respectively,
SEQ ID NOs: 594, 595, 7, and 7, respectively,
SEQ ID NOs: 596, 597, 7, and 7, respectively,
SEQ ID NOs: 598, 599, 7, and 7, respectively,
SEQ ID NOs: 636, 637, 7, and 7, respectively,
SEQ ID NOs: 640, 641, 7, and 7, respectively,
SEQ ID NOs: 706, 707, 7, and 7, respectively,
SEQ ID NOs: 712, 713, 7, and 7, respectively,
SEQ ID NOs: 753, 754, 7, and 7, respectively, and
SEQ ID NOs: 757, 758, 7, and 7, respectively.” (i.e., Claims 1-12, and 15-16);
-AND-
“A fusion protein comprising a) two biparatropic antigen-binding sites and b) two Fc domains, wherein the fusion protein comprises the polypeptides of the following structural formulas (I'), (II'), (III), and (IV):
N'-VD1-(L3)p-X-(L1)n-A-C' (I');
N'-VD2-(L4)q-Y-(L2)m-B-C' (II');
N'-C-C' (III); and
N'-D-C' (IV)
wherein, in the structural formulas (I'), (II'), (III), and (IV),
N' is the N-terminus of each polypeptide,
C' is the C-terminus of each polypeptide,
- refers to a linkage,
A, B, C, and D are monomeric polypeptide sequences of an Fc domain each comprising the CH2 and CH3 regions of an immunoglobulin, wherein A and B comprise a knob variant and C and D comprise a hole variant that promotes the formation of an Fc heterodimer (heterodimeric Fc); wherein A forms a dimer with one of C or D to form the first Fc domain, and B forms a dimer with the remaining one of C or D to form the second Fc domain;
L1, L2, L3, and L4 are each [a] peptide linker,
n, m, p, and q are each independently 0 or 1,
VD1 is a first polypeptide sequence of the second antigen-binding site, which consists of a VH comprising HCDR1, HCDR2, and HCDR3;
VD2 is a second polypeptide sequence of the second antigen-binding site, which consists of a VL comprising LCDR1, LCDR2, and LCDR3;
wherein VD1 and VD2 pair with each other to form a second antibody variable region that specifically binds to a second antigen,
X is a first polypeptide sequence of the first antigen-binding site, which comprises heavy chain CDR1, CDR2, and CDR3 sequences or a heavy chain variable region comprising HCDRs1-3;
Y is a second polypeptide sequence of the first antigen-binding site, which comprises light chain CDR1, CDR2, and CDR3 sequences or a light chain variable region comprising LCDRs1-3;
wherein X and Y pair with each other to form the a first antibody variable region that specifically binds to a first antigen;
wherein the polypeptides of (I’), (II’), (III), and (IV) comprise the sequences selected from the group consisting of:
SEQ ID NOs: 53, 65, 7, and 7, respectively,
SEQ ID NOs: 57, 61, 7, and 7, respectively,
SEQ ID NOs: 57, 65, 7, and 7, respectively,
… and,
SEQ ID NOs: ….” (i.e., similar to the above amended claim, all the functional biparatropic sequences are listed) (claims 13-14 and 17);
-AND-
“A transformed cell expressing the fusion protein according to claim 1.” (amended claim 1 and 20);
-AND-
“A transformed cell expressing the fusion protein according to claim 13.” (amended claim 13 and 20);
-AND-
“A method for treating cancer, comprising administering to a subject in need thereof, a therapeutically effective dose of the fusion protein according to claim 1.” (amended claim 1 and 21);
-AND-
“A method for treating cancer, comprising administering to a subject in need thereof, a therapeutically effective dose of the fusion protein according to claim 13.” (amended claim 13 and 21); does not reasonably provide enablement or support for more. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention. Dependent claims 2-17 and 19-21 are also rejected since they are dependent on claim 1 but do not remedy the deficiencies.
With regard to antibodies, it should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. In the instance of a bispecific or biparatropic antibody, it is well known in the art that such a construct comprises two pairs of VH/VL regions (i.e., one pair for each binding domain) and each VH/VL pair consists of six CDRs for a total of 12 CDRs (Brinkmann, et al., MABS, 2017, 9, 182-212, see p 183, col 1, ¶1 and Fig 1-2). 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 parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff, et al., PNAS, 1982, 79, 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves. Furthermore, the pairing propensity of any two given germlines depends to a large extent on the sequence and conformation of HCDR3, which is highly variable and if HCDR3 is fixed, different VH/VL pairs can result in significant stability differences (Chiu, et al., Antibodies, 2019, 8, 1-80, Section 2.1.3). Therefore, the art supports that the nondegenerate CDR sequences for each antigen binding domain and the specific pairing of the VH and VL sequences for each antigen binding domain are necessary structural features to maintain functional binding.
For example, below is an alignment of six HCDR3 sequences of an anti-HER2 antibodies disclosed in US 2011/0217305 (Pedersen, et al., 08SEP2011). Despite sharing the same immunogen (HER2) the resulting antibodies share little similarity at the sequence level:
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.
Artisans are well aware that knowledge of a given antigen (for instance a specific epitope of HER2 or any antigens listed in claim 7) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably represent the breadth of the genus of antibodies that bind the given antigen in the instant application.
It is noted that applicant has also claimed a method of administering a product. However, artisans must reasonably be in possession of a product in order to be in possession of methods of administering said product. As has been discussed above, the broadest claims describe the administered product based upon what it does, such as binding to essentially any antigen. However, as has been made clear by recent court cases as well as USPTO guidance, describing an antibody simply by what it binds is not sufficient to provide adequate written description for the recited genus. Indeed, as taught by Edwards et al., Lescar et al., and Goel et al., the number of potential antibody structures (i.e., sequences) which can bind to the same antigen is literally astronomical. As such, describing the administered reagent based upon what it binds, where it binds, or its function as an inhibitor fails to necessarily provide a structure that gives rise to the aforementioned properties.
Furthermore, the literature teaches that treatment provides increased control over a disease in patients that already have the disease (i.e., cancer), prevention reduces the probability of a disease-free patient from getting the disease (i.e., cancer), and that while antibodies directed to HER2, for example have shown clinical promise to treat cancer, evidence for prevention of the disease is not discussed. Specifically, it is well known in the art, that cancer treatment refers to the use of interventions (e.g., chemotherapy, radiation therapy, surgery, immunotherapy, or a combination thereof) to eliminate or control cancer cells that are already present in the body; whereas cancer prevention is an action taken (e.g., changes in diet and lifestyle, screening, chemoprevention) to lower the chance of getting cancer (see entire documents: NIH-NCI, Cancer Prevention Overview, 2023; Mayo Clinic, Cancer Treatment, 2024; and NCFR ,Cancer Intervention vs Prevention: What does it Mean?, 2024). The prior art does not teach antibodies for preventative uses in cancer.
The specification discloses the specific sequences of fusion proteins comprising mono or biparatropic antigen binding sites and two Fc domains. In certain instances, the fusion proteins failed to form, despite considerable knowledge of the constructs and in other instances, the fusion protein failed to function (i.e., bind one or both epitopes with high affinity). Therefore, the fusion proteins generally lack predictability, and the prior art supports that antigen binding constructs comprising antibody or antibody fragments require six nondegenerate CDRs for a monospecific antibody and twelve nondegenerate CDRs for a bispecific antibody, thus it would require undue experimentation for one of ordinary skill in the art to make and/or use the fusion proteins as instantly claimed. Therefore, claims 1-17 and 19-21 as presently claimed are rejected because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-12, 15, and 19-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2012/116926 A1 (F. HOFFMANN-LA ROCHE AG, et al., 07SEP2012, included in IDS), herein referred to as “’926.”
‘926 teaches antigen binding proteins comprising two Fc domains and two antigen binding domains, wherein the antigen binding domains comprise MET or HER3 (p 32-33) and wherein the encircled structure
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of Fig 1 of ‘926 teaches the structure of instant claim 1 (i.e., an antigen-binding site consisting of a first and second polypeptide comprising at least one CDR, wherein the first and second polypeptide form a dimer, and the antigen-binding site is capable of specifically binding to a target antigen, a first Fc domain consisting of two sequences, one of which is bound to the first polypeptide of the antigen-binding site, and a second Fc domain consisting of two polypeptide sequences, one of which is bound to the second polypeptide of the antigen-binding sequence) as well as dependent claims 2-5, 7-8, 11-12, and 15. Furthermore, ‘926 teaches that the Fc part of the modified HCs are of IgG1 isotype and may encompass knob-in-holes and electrostatic steering mechanisms for improved pairing (p 6, p 10, and p 11). Accordingly, ‘926 teaches that the antigen-binding protein may be expressed using a transformed cell (p 27 and claim 18). ‘926 also teaches the use of the multiple Fc structure for the treatment of cancer, comprising the administration of the antigen-binding protein and pharmaceutical compositions thereof (p 29-30).
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, (i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter (e.g., improved antitumor activity compared to an IgG-based antibody of a conventional structure having the same antigen-binding site)), if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Therefore, the prior art anticipates the invention as presently claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571)272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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