Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Sep. 12, 2024. Claims 1-20 are pending and currently examined.
Specification – Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) as follows:
The specification does not contain sequence identifiers (SEQ ID NO:) in all locations where sequences are disclosed, see at least FIGs 2E and 14A. To correct this, the sequences in figures can be referred to in either the figure or the Brief Description of Drawings. If the prior filed Sequence Listing does not contain updated sequences, Applicant is also required to submit a replacement Sequence Listing that includes all updated sequences.
Full compliance with the sequence rules is required in response to this Office Action. A complete response to this office action should include both compliance with the sequence rules and a response to the Office Action set forth below. Failure to fully comply with both these requirements in the time period set forth in this Office Action will be held non-responsive.
Analysis of Claims and Disclosure
The base claim 1 is directed to a binding molecule capable of specifically binding to postfusion hemagglutinin (HA), wherein the binding molecule binds to the stem region of HA; and wherein the stem region of HA comprises an epitope comprises a β-hairpin. This claim is highly generic, encompassing any binding molecule that specifically binds to a postfusion hemagglutinin (HA) that comprises a stem (stalk) region comprising a β-hairpin. The claim is generic even to where the HA is from.
Although claim 1 requires that the binding molecule binds to the stem region of HA, the claim does not require that the binding molecule binds to an epitope that comprises a b-hairpin. Based on the wording, claim 1 only specifies that that stem region of HA comprises an epitope that comprises a b-hairpin. Therefore, the claim 1 is interpreted to read on a binding molecule that binds to a postfusion HA which comprises a stem region comprising a b-hairpin.
The instant specification teaches that the Applicant screened and isolated antibodies from Bmem cells (memory B cells) from PBMCs of human donors. See [0341]. It teaches that, to identify IAV- and IBV-cross-reactive HA Abs, individual HA-binding IgG+ memory B (Bmem) cells sorted from peripheral blood mononuclear cells (PBMCs) of eight human donors before or 1-2 weeks after seasonal influenza vaccination were cultured, and that a multiplex binding assay was used to screen the secreted clonal IgGs for reactivity against a panel of recombinant HAs (rHAs). See [0375].
The instant specification teaches that from eight donors, 1,642 IgG+ HA-binding cultures were recovered, that two clonal Abs (S1V2-72 and K06.18), from unrelated donors, were identified that bound rHAs from group 1 (H1 and H5) and group 2 (H3) IAV strains, as well as from the Victoria and Yamagata lineages of IBV (FIG. lA). See [0376]. It teaches that S1V2-72 is encoded by IGHV1-2*02/IGHD5- 12*01/IGHJ5*02 and IGLV2-23*01/IGLJ3*02, with 10.5% and 3.8% somatic mutations in the heavy (H) and light (L) chain variable genes, respectively; and that K06.18 is encoded by similar V(D)J rearrangements (IGHV1-2*07/IGHD6-13*01/IGHJ4*02 and IGLV2-23*01/IGLJ3*02) and is also substantially mutated in the H-(6.0%) and L-chain (4.7%) variable regions (McCarthy K R, et al. (2018) Immunity 48:174-184 e179). See [0377].
A post-filing reference from the inventors, Finney et al. (PNAS, 2024, 121(1): e2316964120), discloses a study that is related to the instant invention. Finney teaches identification and characterization of B cells, from four unrelated individuals, secreting IgGs that bind cell-surface expressed HA from various IAV subtypes and from both IBV lineages. According to Finney, the IgGs bind the corresponding postfusion HA2s in vitro, as well as the recombinant, soluble, HA0 trimeric ectodomains in Luminex and enzyme-linked immunosorbent assays (ELISAs), and that the structure of a Fab from one of the IgGs (S1V2-72) bound with the “EHA2” recombinant mimic of postfusion HA2 defines the epitope as a β-hairpin loop; this β-hairpin is also present on the prefusion HA trimer, but it is occluded at the membrane-proximal end of the molecule. The fusogenic conformational change translocates this loop to the membrane-distal end of the postfusion form. S1V2-72 IgG does not neutralize infectivity in vitro but confers Fc-dependent protection from lethal challenge by either an IAV or an IBV. See page 2, left column, para 1.
Based on the Specification, antibody S1V2-72 has an VH of SEQ ID NO: 5 and an VL of SEQ ID NO: 17; while antibody K06.18 has an VH of SEQ ID NO: 6 and an VL of SEQ ID NO: 18. See Tables 1 and 2. For antibody S1V2-72, SEQ ID NO: 5 comprises CDR sequences of SEQ ID NOs: 59-63 and SEQ ID NO: 17 comprises CDR sequences of SEQ ID NOs: 64-65 and 67-69. For antibody K06.18, SEQ ID NO: 6 comprises CDR sequences of SEQ ID NOs: 70-74 and SEQ ID NO: 18 comprises CDR sequences of SEQ ID NOs: 75-76 and 78-80. See below:
SEQ ID NO:5 (VH of S1V2-72)
SEQ 59/60 seq 61/62
QVQLVQSGAELKKPGASVKVSCKASGYTFTGNYIHWMRQVPGQGLEWMGWINPRTGDTHHAQKFQGRVDMTRDTSINTAYLELTRLESDDTALYYCARCVFATSQFDPWGQGTLVTVSS
Seq 63
SEQ ID NO:17 (VL of S1V2-72)
Seq 64/65 seq 67
QSALTQPASVSGSPGQSITISCTGTNSDIGSHNLVSWYQQHPGKAPKVMIYDDSKRPSGVSNRFSGSKSGSTASLTISGLQSEDEADYYCCSYAGSSNWVFGGGTKLTLL
Seq68/69
SEQ ID NO:6 (VH of K06.18)
Seq 70/71 seq72/73
EVQLVQSGAEVKKPGASVRVSCRASGYSFTDNYIHWVRQAPGQGLEWMGWINPDSGATSYEHKFQGRVTMTRDTSISTAFMELGSLRSDDTAVYYCARVRRGTAGLDYWGQGTLVTVSS
Seq 74
SEQ ID NO:18 (VL of K06.18)
Seq75/76 seq 78
QSVLTQPASVSGSLGQSITISCTGTSSDIGNYNLVSWYQQHPGQAPKLIIYEVNRRPSGVSDRFSDSKSGNTASLTISGLQAEDEGDYYCFSYAGGSTWVFGGGTKVTVL
Seq79/80
According to the teachings of the instant Specification as well as Finney, the binding molecule of the claimed invention reads on the B cell antigen receptors on the memory B cells (Bmems); and the binding of an antibody to postfusion HA stem b-hairpin region correlates with the activity to bind an EHA2 peptide, which is recombinant mimic of postfusion HA2 comprising the b-hairpin region.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter because it is directed to a judiciary exception.
A claim directed to a judicial exception must be analyzed to determine whether the elements of the claim, considered both individually and as an ordered combination, are sufficient to ensure that the claim as a whole amounts to significantly more than the exception itself. To be patent-eligible, a claim that is directed to a judicial exception must include additional features to ensure that the claim describes a process or product that applies the exception in a meaningful way, such that it is more than a drafting effort designed to monopolize the exception.
As indicated in the “Analysis of Claims and Disclosure” above, the binding molecule of claims 1-16 read on an antibody molecule that naturally exist in a B cell (B cell antigen receptor), particularly in Bmem, in human body. Claim 16, which is directed to a pharmaceutical formulation comprising the binding molecule of Claim 1, does not specify additional element in addition to the binding molecule. It also reads on naturally occurring product, e.g., PMBCs containing the Bmem with the specific antibody.
Therefore, claims 1-16 are unpatentable because they read on a naturally occurring product.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 1-16 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). As indicated above, claims 1-16 read on B cell antigen receptors on Bmem in human subjects. So, the claims read on human organism.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 8-9, 11 and 13 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
These claims specify CDRs comprising sequences of SEQ ID NO: 66 or 77. However, these two sequence identifiers do not specify any sequence. Therefore, claims 8-9, 11 and 13 are indefinite.
Note: SEQ ID NOs: 66, 77, 88, 99, 110, 121, 132, 143, 154, 165 and 176 do not specify any sequence.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
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, disclosure of drawings or structural chemical formulas, or by disclosure of relevant, identifying characteristics, i.e., complete/partial structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, by predictability in the art, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
In Regents of the University of California v. Eli Lilly and Co. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997), the Court decided that adequate written description of genetic material "requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention." Id. 43 USPQ2d at 1404 (quoting Fiefs, 984 F.2d at 1171, 25 USPQ2d at 1606). In AbbVie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (Court of Appeals, Federal Circuit 2014), the Court ruled that “[W]ith the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that “merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries.”).”
Claims 1-2 and 16-20 are directed to a binding molecule capable of specifically binding to postfusion hemagglutinin (HA), wherein the binding molecule binds to the stem region of HA, and wherein the stem region of HA comprises an epitope comprises a β-hairpin. Claims 3 and 14-15 specify that the binding molecule comprises CDRs, indicating that it is an antibody-related binding molecule. Claims 4-13 specify antibody VH, VL and/or CDR sequences, but with high level of changes.
The instant specification discloses 12 antibody clones isolated from memory B cells from human subjects, i.e., S1V2-72 comprising VH of SEQ 5 and VL of SEQ 17, K06.18 comprising VH of SEQ 6 and VL of SEQ 18; 334-100 comprising VH of SEQ 7 and VL SEQ 19; 350-310-D7B comprising VH of SEQ 8 and VL of SEQ 20; 350-315 comprising VH of SEQ 9 and VL of SEQ 21; 350-376 comprising VH of SEQ 10 and VL of SEQ 22; M94 comprising VH of SEQ 11 and VL of SEQ 23; Cl-ID26079-156194 comprising VH of SEQ 12 and VL of SEQ 24; FDA053-87001 comprising VH of SEQ 13 and VL of SEQ 25; 351-52 comprising VH of SEQ 14 and VL of SEQ 26; 350-341 comprising VH of SEQ 15 and VL of SEQ 27; and S5V6-P7F12 comprising VH of SEQ 16 and VL SEQ 28. See Table 1 and 2. The specification also discloses H and L chain CDRs associated with each of the antibodies. See Tables 3-14.
The specification does not provide information disclosing what the claimed variations in the CDRs can be, and what combinations of VH, VL and CDR sequences can be except for the combinations associated with the disclosed antibody clones. The specification does not provide guidance on how these critical sequences can be modified by amino acid substitution, addition or deletion without changing the antigen binding properties of the original antibody. Therefore, the claims encompass a vast number of antibodies that have not been described in the specification, even encompassing non-antibody molecules not known in the art at the time of invention.
The art relating to antibodies recognizes that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity that is characteristic of the parent 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. 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. (Proc. Natl. Acad. Sci. U.S.A., 1982, 79:1979-1983). Rudikoff et al. teaches 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. The teachings in the art therefore indicate that the presence of both the heavy chain and light chain variable regions, with the indicated CDRs of those regions in the proper conformation, is required for the antigen binding proteins to bind the target antigens.
Accordingly, the specification does not provide written description support that the Applicant is in possession of the binding molecules in a generic form in claims 1-20.
Scope of Enablement
Claims 1-2 and 16-20 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 antibodies that specifically binds to the stem region of HA and wherein the stem region of HA comprises an epitope comprises a β-hairpin, does not reasonably provide enablement for a highly generic binding molecule that is not antibody-related. 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.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wriqht, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention, 5) the state of the prior art, 6) the relative skill of those in the art, 7) the predictability of the art, and 8) the breadth of the claims. Id. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
M.P.E.P. §2164.03 [R-2] states: [I]n applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soil, 97 F.2d 623,624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488,496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991 ). A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
The nature of the invention is a binding molecule capable of specifically binding to postfusion hemagglutinin (HA), wherein the binding molecule binds to the stem region of HA, and the stem region of HA comprises an epitope comprises a β-hairpin. The invention also relates to a method of treating a subject comprising administering to the subject a pharmaceutical composition comprising the binding molecule.
The specification provides working examples on developing human monoclonal antibodies from Bmem cells from human donors. The specification does provide working examples for obtaining binding molecules with the same activity other than antibody molecules. The specification does not provide guidance on how molecules other than ones related to antibodies can be identified, produced, and/or used in treatments. The technique for producing non-antibody binding molecules with the claimed specificity is unpredictable and takes undue experimentation from highly skilled researchers, especially for a binding molecule that itself is not defined.
Therefore, the specification does not provide sufficient guidance to allow one skilled in the art to practice the claimed invention on the full scope with a reasonable expectation of success and without undue experimentation. In the absence of such guidance and evidence of working examples, the specification fails to provide an enabling disclosure commensurate in scope with the claim.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-5 and 16 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Guthmiller et al. (US 2025/0059260 A1, published on Feb. 20, 2025; PCT filed on Dec. 21, 2022).
The claims are interpreted as indicated in the “Analysis of Claims and Disclosure” above.
Guthmiller teaches that broadly neutralizing antibodies (bnAbs) targeting epitopes of the influenza virus hemagglutinin (HA) have the potential to provide near universal protection against influenza virus infection. However, viral mutants that escape bnAbs have been reported. The identification of bnAb classes that can neutralize viral escape mutants is critical for a distinct class of bnAbs targeting a discrete membrane proximal anchor epitope of the HA stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with pandemic-threat H2 and H5 viruses. Antibodies targeting this anchor epitope utilize a highly restricted repertoire, which encodes for two public binding motifs that make extensive contacts with conserved residues in the fusion peptide. Moreover, anchor epitope-targeting B cells are common in the human memory B cell (MBC) repertoire and were recalled in humans by an oil-in- water adjuvanted chimeric HA (cHA) vaccine, a potential universal influenza virus vaccine. To maximize protection against seasonal and pandemic influenza viruses, vaccines should aim to boost this previously untapped source of bnAbs that are widespread in the human MBC pool. See [1933].
Guthmiller discloses a large number of monoclonal antibodies defined by heavy chain/light chain CDRs (HCDR/LCDR) or variable regions (VH/VL). See [0033]-[1898]. One of these antibodies is defined by SEQ ID NO: 1380 and SEQ ID NO: 7012 (see page 158, right column), which are identical to SEQ ID NO: 14 and SEQ ID NO: 26 of the instant invention, respectively. Here, the instant SEQ ID NOs: 14 and 26 are, respectively, amino acid sequences of VH and VL of the monoclonal antibody 351-52 of the instant invention. See e.g., Table 1 and Table 2.
Since Guthmiller discloses an antibody that has the same VH/VL sequences as the monoclonal antibody 351-52 of the instant invention, the antibody of defined by SEQ ID NO: 1380 and SEQ ID NO: 7012 in Guthmiller is considered to have the same binding properties of the instant antibody 351-52, which comprises a set of VH/VL specified in instant claims 4-5 (which recite SEQ ID NOs: 14 and 26).
Accordingly, Guthmiller anticipates claims 1, 3-5 and 16.
Claims 1-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by McCarthy et al. (Immunity 48, 174–184, January 16, 2018; submitted in IDS filed on Jul. 29, 2025).
McCarthy is referred to by the instant specification and Applicant’s post-filing publication, Finney et al., to disclose the antibody K06.18 of the instant invention. See discussions in the “Analysis of Claims and Disclosure” above.
McCarthy teaches that Human B cell antigen-receptor (BCR) repertoires reflect repeated exposures to evolving influenza viruses; new exposures update the previously generated B cell memory (Bmem) population. Despite structural similarity of hemagglutinins (HAs) from the two groups of influenza A viruses, cross-reacting antibodies (Abs) are uncommon. The authors analyzed Bmem compartments in three unrelated, adult donors and found frequent cross-group BCRs, both HA-head directed and non-head directed. See Abstract.
McCarthy teaches that to characterize the BCR repertoire for recombinant influenza HA (rHA)-specific, IgG+ Bmem cells, the authors sorted PBMCs from three unrelated, healthy donors who had received the 2014-15 TIV (KEL01 and KEL03) or the 2015-16 TIV (KEL06) two weeks before blood collection. They used PE-labeled rHA (H3N2 A/Wisconsin/67/2005, henceforth designated ‘‘H3 WI-05’’) to enrich rHA-specific B cells, depositing one rHA+CD19+CD27+CD24hiIgM-IgD-IgG+ memory cell per well (Figures 2A and S1A). Clonal IgGs that were later secreted into culture supernatants were individually screened against a panel of 10 rHA proteins in a multiplex bead assay (Figure 2B and Figure S1B). See para bridging pages 175-176. McCarthy teaches that the epitopes of crossreactive Bmem clones from KEL06 were more evenly distributed between head (7/18) and non-head (11/18) (Figure 3A and Table S1). See para bridging pages 176-177. Fig. 3A shows 18 Bmem clones from donor KEL06, including clone K06.18 which is disclosed in the instant disclosure and post-filing publication, Finney et al., as reading on the binding molecule as claimed.
McCarthy further teaches the CDR3 sequences as well as the germline origins of V-D-J for the VH and VL regions of the CDR3 sequences for the Bmem clones from KEL06, including clone K06.18. See Figure S4 below:
PNG
media_image1.png
862
1510
media_image1.png
Greyscale
Both the sequences of HCDR3 and LCDR3 of K06.18 are comprised in instant SEQ ID NOs: 6 and 18, respectively.
Regarding claim 2, neither McCarthy nor the instant disclosure and the post-filing publication Fanney disclose if the clone K06.18 binds to a postfusion HA with a stem region comprising a b-hairpin epitope comprising the sequence set forth in SEQ ID NO; 191 (which is AXDXGNGCFEX). On the other hand, McCarthy teaches that recombinant HA (rHA) from H3N2 A/Wisconsin/67/2005 was used to enrich rHA-specific B cells in the screening process (see discussion above), suggesting that the Bmem clones isolated in the screening process are likely to bind of rHA of H3N2 A/Wisconsin/67/2005.
GenBank: AIU46082.1 discloses the amino acid sequence of hemagglutinin of influenza virus A/Wisconsin/67/2005(H3N2). The HA sequence comprises AEDMGNGCF which is highly reminiscent of SEQ ID NO: 191.
The Office does not have the facilities and resources to provide the factual evidence needed in order to establish that the clone K06.18 of McCarthy does not bind a postfusion HA with a stem region comprising a b-hairpin epitope comprising the sequence set forth in SEQ ID NO: 191. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed binding molecule is different from that 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).
Regarding claim 16, which is directed to a pharmaceutical formulation comprising the binding molecule of Claim 1, it does not specify additional element in addition to the binding molecule. It also reads on a composition containing the clone K06.18.
Accordingly, McCarthy anticipates claims 1-16.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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.
Claims 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Guthmiller et al. (US 2025/0059260 A1, published on Feb. 20, 2025; PCT filed on Dec. 21, 2022) and McCarthy et al. (Immunity 48, 174–184, January 16, 2018; submitted in IDS filed on Jul. 29, 2025), as applied above, in view of Nishiyama et al. (Vaccine 41 (2023) 4525–4533) and GenBank: ABV02199.1 (hemagglutinin, partial [Influenza A virus (A/chicken/Nigeria/VRD203/2006(H5N1))]. Dated Jul. 26, 2016)
These claims are directed to a method for treating a subject, comprising: administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical formulation comprising the binding molecule of claim 1.
Relevance of Guthmiller and McCarthy is set forth supra.
Guthmiller further teaches methods of treating disorders by administering antibodies. See [2007]-[2008]. Guthmiller teaches that the therapeutic compositions and treatments disclosed therein may precede, be co-current with and/or follow another treatment or agent by intervals ranging from minutes to weeks. In embodiments where agents are applied separately to a cell, tissue or organism, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the therapeutic agents would still be able to exert an advantageously combined effect on the cell, tissue or organism. See [2081].
Nishiyama teaches that post-fusion influenza vaccine adjuvanted with SA-2 confers heterologous protection via Th1-polarized, non-neutralizing antibody responses. Nishiyama teaches that a variety of vaccine antigens are designed to increase the antigenicity of conserved epitopes to elicit cross-protective antibodies that often lack virus-neutralizing activity. Given the contribution of antibody effector functions to cross-protection, adjuvants need to be added to modulate antibody effector functions as well as to enhance antibody quantity. The authors previously showed that post-fusion influenza vaccine antigens elicit non-neutralizing but cross-protective antibodies against conserved epitopes. Here, using a murine model, they comparably assessed the adjuvanticity of the newly developed SA-2 adjuvant containing a synthetic TLR7 agonist DSP-0546 and squalene-based MF59 analog as representative Th1- or Th2-type adjuvants, respectively. Both types of adjuvants in the post-fusion vaccine comparably enhanced cross-reactive IgG titers against heterologous strains. However, only SA-2 skewed the IgG subclass into the IgG2c subclass in association to its Th1-polarizing nature. SA-2-enhanced IgG2c responses exhibited antibody-dependent cellular cytotoxicity against heterologous virus strains, without cross-neutralizing activity. Eventually, the SA-2- adjuvanted vaccination provided protection against lethal infection by heterologous H3N2 and H1N1 viruses. Together, the authors conclude that the combination with a SA-2 is advantageous for enhancing the cross-protective capability of post-fusion HA vaccines that elicit non-neutralizing IgG antibodies. See Abstract.
Nishiyama teaches that the post-fusion HA-split vaccines were manufactured by Sumitomo Pharma. Co., Ltd. (Japan). To produce HA-split vaccines (H1N1: A/Guangdong-Maonan SWL1536/2019 and H3N2: A/Hong Kong/2671/2019), purified live viruses were suspended in 0.1% Tween 80 and mixed with ether. After stirring, the mixture was centrifuged to separate the aqueous and ether phases and the ether phase was discarded. After several rounds of extraction, the remaining aqueous phase was collected as HA-split vaccine. For the post-fusion HA-split vaccine, the vaccines were treated with citrate buffer and adjusted below pH 5.5 to cause irreversible transition into the post-fusion form (fH1 and fH3). See page 4526, right column, para 2.
Nishiyama teaches that the primary limitation of this study is the lack of direct linkage between Fc-mediated ADCC functions and cross-protection provided by non-neutralizing IgG antibodies. This point needs to be addressed in future experiments using FccR knock-out mice, as the authors have previously demonstrated the linkage by a TLR9 agonist-adjuvanted vaccine. Furthermore, the possible contribution of cellular immunity (CD4 and CD8 T-cell responses) to enhancing the protection by cross-reactive IgG cannot be excluded. However, they have previously observed in antibody-infusion experiments that those circulating antibodies did contribute to the cross-protection provided by post-fusion HA vaccines. In addition, under similar challenge conditions, the vaccine adjuvanted with TLR9 agonist conferred cross-protection even after depletion of CD8+ T-cells by antibody treatment. Together, these data support the idea that non-neutralizing IgG antibodies with ADCC activity indeed contribute to the cross-protection provided by Th1-polarizing adjuvants, such as TLR7/8 and TLR9 agonists. The data in this study have great implications for the future development of influenza vaccines and incorporation of immunopotent adjuvants that can confer broader protection against IAV infections by inducing higher levels of non-neutralizing but cross-protective IgG antibodies. See page 4532, left column, para 2.
Accordingly, teachings of Nishiyama indicate that vaccination of a post-fusion influenza virus HA vaccine would provide protection to viral challenges, and suggest that non-neutralizing antibodies with antibody-dependent cellular cytotoxicity (ADCC) activity contribute to cross-protection of viral infections.
GenBank: ABV02199.1 discloses amino acid sequence of an influenza A virus hemagglutinin, which comprises the sequence of SEQ ID NO: 57 specified in claim 20, indicating that an influenza A virus with the claimed HA sequence exists and circulates in nature.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Guthmiller, McCarthy and Nishiyama to arrive at the invention as claimed. One would have been motivated to do so to investigate the potential of monoclonal antibodies disclosed in Guthmiller and McCarthy in the treatment of influenza virus infection.
Regarding claim 20, Nishiyama teaches that administration of post-fusion influenza HA vaccine provide protection to viral challenges, while GenBank: ABV02199.1 indicates that an influenza A virus strain with an HA comprising SEQ ID NO: 57 as claimed exists and circulates in nature. One skill in the art would have found it obvious to combine the administration of antibodies disclosed in Guthmiller and McCarthy with administration of the post-fusion HA vaccines disclosed in Nishiyama in a treatment process so that the protective activities of both the antibodies and vaccines may be combined. As to the HA proteins with the claimed sequences, one of skill in the art would have found it obvious to introduce the HA disclosed in GenBank: ABV02199.1 into the study in case that an influenza virus with the HA sequence enters circulation and causes human infection.
Relevant Prior Art Reference
The following prior art reference not relied upon in the current rejection is made of record here:
Adachi et al. Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies. Nat. Commun., 2019, 10:3883. Submitted in IDS filed on Jul. 29, 2025.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
Prosecution Insights