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 .
Application Status
Claims 1-19 are pending and examined on the merits herein.
Power of Attorney
It is noted that a Power of Attorney is not on record for the instant application. The Applicant is encouraged to file a Power of Attorney in the event that the Examiner needs to communicate with an authorized representative for the Applicant during the prosecution of the case.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 45. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term affibodies™ on page 10, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because the reference to the sequence listing refers to the size of the file in kilobytes (kb), but the size is required to be in bytes.
Appropriate correction is required.
Claim Objections
Claims 3, 5, 9, 12, 16, and 19 are objected to because of the following informalities:
Regarding claims 3 and 14: Claims 3 and 14 do not end with a period. Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola V. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995); MPEP 608.01(m).
Regarding claim 5, the claim recites: “(a) the antibody has four antigen-binding region”, but should read “the antibody has four antigen-binding regions”;
Regarding claim 9, the claim recites: “the binding molecule of claim 2, where the binding molecule”, but should read “the binding molecule of claim 2, wherein the binding molecule”; further claim 9 recites “and” between options i) and j), this should be an “or;
Regarding claim 12, option (b) recites “polypeptides in table 12, all of the CDR sets”, but should read “ polypeptides in table 12, or all of the CDR sets” and option (c) recites “polypeptides in table 12, all of the CDR sets”, but should read “ polypeptides in table 12, or all of the CDR sets”;
Regarding claim 16, the claim recites a list of options (a)-(h) but includes two “or” at options (e) and (g); the “or” at the end of option (e) should be deleted;
Appropriate correction is required.
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 15-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the statement “ the use” or “for use” of an invention without any meaningful steps for that use does not qualify as a process, machine, manufacture or composition of matter.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 7-8, 10-14, 16, and 19 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.
Regarding claims 7, 16, and 19, the phrase "preferably" 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(d).
Regarding claims 8 and 10-14, references tables and/ or figures in the claims from the specification. MPEP 2173.05 (s) indicates where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant' s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
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.
Claims 1-11 and 13-19 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. This is a written description rejection.
Claimed Invention
Claims 1-2 are drawn to a genus of trispecific single domain antibodies, specifically a set of VHH that bind to IL-2A, IL-2B and IL2G antigens.
Claims 3-9 and 15-19 depend from claim 2 without resolving the issue identified above and are therefore included in this rejection.
Claims 10-11, are drawn to a partial resolution of the issue identified above but only requires sequence for one of the antigen targets in the trispecific; and are therefore included in this rejection.
Claim 13 is drawn to the VHH domain sequences or variants thereof.
Claim 14, is drawn to CDRs as shown in Figure 12C or variant CDRs or the CDRs in Table 12 or variants thereof.
Breadth of Claims
The invention as disclosed in claims 1-2 recites binding to IL2A, IL2B and IL2G.
One of ordinary skill in the art would understand that the 3 CDRs of a single domain antibody are responsible for antigen binding characteristics, including specific epitope binding. The claim does not disclose the structure associated with the claimed function. The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision sequences, particularly in the 3 CDR regions, such that the obtained structure would result in the claimed functions.
Scope of Disclosed Species
The instant specification discloses that llama phage display libraries were generated against the different subunits of the human IL-2R and VHH fragments were identified by screening with human and mouse IL-2RA, IL-2RB and IL-2RG antigens (page 68, section B). The instant specification further discloses Table 3 with the amino acid sequences of monovalent VHHs for all three antigens 13 for IL-2RA, 13 for IL-2RB and 12 for IL-2RG (pages 84-86) and table 4 with the sequences of the CDRs and the framework for the clones from table 3. Table 5 discloses the sequence of multispecific polypeptides (page 91-93). Table 7 discloses the CDRs and VH for patent clones 1-13, and 39-110; table 8 discloses the CDRs and VH for patent clones 14-26 and 111-312; and table 9 discloses CDR and VH for patent clones 27-38 and 313-466. The anti-IL2R VHH single domain antibodies in the disclosure with 100% sequence identity in the CDR regions of the heavy chain variable regions represent the anti-IL-2RA, IL-2RB, IL-2RG single domain antibodies that the applicant was in possession of at the time of filing.
State of the Prior Art
VHH Antibodies
At the time of filing, VHH antibody antigen binding domain functionality was known to depend on the entire structure, particularly a full complement of three CDRs. It is understood by one of ordinary skill in the art that that uncharacterized CDR binding is unpredictable and that each construct requires function testing.
Bever et al. (Anal Bioanal Chem (2016) 408:5985–6002; hereinafter “Bever”) teaches VHH antibodies, and the production and screening thereof [e.g., title, abstract]. Bever teaches Nanobodies® are VHH domain antibodies that are heavy chain only (e.g. HcAb) that are naturally produced by camelids and sharks [e.g., pg. 5985, “Introduction”]. Bever teaches the overview of process of making VHH antibodies wherein (1) an alpaca is the camelid species, (2) mRNA is collected from the alpaca and a cDNA library is constructed therefrom, (3) VHH genes are isolated, (4) a phage-display VHH library is generated, (5) solid phase panning conducted to select the desired VHH, and (6) desired VHH is obtained [e.g., fig. 2].
Hacisuleyman and Erman (Journal of Biological Physics (2020) 46:189–208; hereinafter “Hacisuleyman”) teaches VHH optimization [e.g., title, abstract]. Hacisuleyman teaches VHH antibodies comprise 3 CDRs which determine target specificity, with CDR3 being the “dominating contributor in antigen recognition” [e.g., pg. 191; fig. 2]. Hacisuleyman further teaches residue numbers for the VHH CDRs may vary, and that in nature CDRs are mutated naturally to increase the binding affinity and specificity towards a target antigen [e.g., pg. 191]. Hacisuleyman teaches that computational screening methods for optimization are a first step that is then followed by experimental strategies [e.g., pg. 191]. Hacisuleyman does not support de novo generation of VHH CDRs to bind a selected antibody, but rather requires the researcher start with a VHH antibody known to bind the target antigen [e.g., 191].
At the time of filing, Ginsberg (WO 2021/030241 A2) taught anti-CD25 (IL-2RA) antibodies were recognized in the art as a promising therapeutic for autoimmune disease (abstract) and disclosed a single clone to that effect PC61, but this clone is not in VHH format (Fig 5). McKeage (BioDrugs 24, 55–76 (2010); PTO-892) teaches that basiliximab (Simulect®) is a recombinant chimeric murine/human IgG1 monoclonal anti-interleukin-2 receptor antibody that is indicated for the prevention of acute organ rejection (abstract) that is the only IL-2RA antibody currently clinically approved that provide intense immunosuppression by inhibiting T lymphocyte proliferation (intro, para 2-3). McKeage further teaches that basiliximab binds specifically and with high affinity to IL-2Rα on antigen-activated T lymphocytes and competitively inhibits IL-2 binding to the receptor, thereby inhibiting IL-2-mediated proliferation of T lymphocytes (section 2, para 3) and further that the specific epitope on IL-2Rα to which basiliximab binds is the seven amino acid string E-R-I-Y-H-F-V at positions 116–122 in the extracellular domain of the α-chain (section 2, para 4). Brauer (WO 2019/092181 A1) taught a bispecific that targets CD122 (IL-2RB) and CD132 (IL-2RG) for prevention of vascular leak syndrome (abstract). Brauer discloses 43 species of anti-CD122 antibody and 20 species of anti-CD132 antibody (table, pages 92-132). Brauer further teaches that the multispecific antigen binding molecules may be in any suitable format including tandem dAb VHH (page 55, line 18). Harris (Sci Rep 11, 10592 (2021); PTO-892) also teaches a bispecific antibody that binds to IL-2RB/G heterodimeric receptor to preferentially promote in vivo expansion of CD8 and NK cells rather than Treg cells as promoted by native IL-2 (abstract and intro). Harris further teaches the screening of 285 anti-IL-2RB and 333 IL-2RG novel heavy chain only antibodies (page 2, para 4). Therefore, the prior art demonstrates that the binding of IL-2RA, IL-2Rb and IL-2RG is possible by various antibodies including single domain format. The prior art does not teach a known structure activity relationship for HCDR1-3 in anti-IL-2RA, IL-2RB or IL-2RG antibody that would allow prediction of CDR residues that specifically bind to these antigens.
Regarding CDR variants:
The CDRs of the VHH interact with framework sequences. These interactions would vary between CDR sequences and changes to the framework sequences would change these interactions resulting in changes to the structure and activity of the VHH (Rouet et. al. Journal of Biological Chemistry. 290(198):11905-11917 (2015) (PTO-892) (Abstract, Figures 5-7). Rouet further teaches that variation in the CDR sequences change the stability of VHH when humanizing a VHH so a consensus framework region of a VHH with variation to the CDRs, as allowed by the claims, would have varying activity as an antibody (page 11915 in col 1 in par 2-4).
Conclusion
As indicated by the art, a full complement of 3 CDRs are required for single domain antibody-antigen binding and one cannot predict all of the possible CDR sequence combinations that will result in a VHH single domain antibody that binds IL-2RA, IL-2RB or IL-2RG.
Further, one skilled in the art would be unable to predict or envision which CDR residues within the claimed CDR consensus sequences may be changed such that the resultant variant CDR may be comprised of an antigen-binding site capable of binding IL-2RA, IL-2RB or IL-2RG. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general, guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, that correlate with the ability to bind IL-2RA, IL-2RB or IL-2RG, and because the disclosed species are not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 3 CDRs in a VHH single domain antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 1-2 would need to recite the 3 CDRs in the VHH single domain antibody that bind IL-2RA, IL-2RB or IL-2RG antigen at the claimed epitope, without variability in the sequences thereof.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-9 and 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Pekar (2021, mAbs, 12(1); PTO-892), Klein (WO 2015/118016 A1; PTO-892), and Harris (Sci Rep 11, 10592 (2021); PTO-892).
Regarding claims 1-2, 6-8, 13-14, Pekar teaches that bi- and multispecific antibodies have recently emerged as promising molecules for disease treatment (discussion, para 1) and that the general modularity of VHHs enables unprecedented possibilities for the construction of bi- and multispecific antibodies which has resulted in a multitude of VHH-based formats with different valencies as well as specificities (page 1, col 1, para 2). Pekar further teaches VHH-derived constructs afford the benefit of multiple reformatting options (discussion, para 1), including a format for multivalent tri-specific VHH antibody (Fig 1E) which corresponds to the instantly claimed Fig 12a, 12. Pekar further teaches that antigen-specific single-domain antibodies from camelids can be readily obtained by combining animal immunization with antibody display systems enabling genotype-phenotype coupling which can then be humanized to lower immunogenicity (discussion, para 1). Pekar further teaches that expression yields were similar to parental molecules of multispecific VHH-based antibodies (page 8, col 1, para 3) and that this VHH-based IgG-like bi-and trispecific antibody platform appears to have the versatility to combine up to three preexisting VHHs in one multispecific molecule (page 9, col 1, para 1).
Pekar does not teach that the trispecific molecule targets IL-2RA, IL2RB and IL-2RG.
Regarding claims 1, 3, 6, and 15-16, Klein teaches with the preferential effect of IL-2 for activating Tregs in vitro and in vivo, the potential for low dose, long-lived IL-2 therapy would seem to have a high prospect for success in autoimmune diseases (page 2, lines 6-8). Klein further teaches that it has been demonstrated that low dose Proleukin® induced Tregs and increased the Treg: Teff ratio, but Proleukin®'s poor PK properties make it suboptimal for maintaining low, consistent levels of IL-2, thus, a new therapeutic approach that re-establishes the natural regulatory T cell (Treg) mediated dominant immune tolerance and severely minimizes any potential stimulatory effects on CD4+ memory T effector cells would greatly enhance the ability to treat patients with autoimmune diseases such as type 1 diabetes, systemic lupus erythematosus (SLE), GVHD, or chronic obstructive pulmonary disease (claims 40-43). Klein further teaches a fusion protein comprising (i) an immunoglobulin molecule, and (ii) two mutant interleukin-2 (IL-2) molecules comprising an amino acid mutation that reduces affinity of the mutant IL-2 molecule to the intermediate affinity IL-2 receptor (IL2RB/G), as compared to a wild-type IL-2 molecule and further that the immunoglobulin molecule is an IgG-class immunoglobulin molecule (claims 1-2),
Regarding claim 9, Klein teaches wherein the IgG has substitutions on the heavy chains and wherein said amino acid substitutions are L234A and L235A (LALA) (claims 16-17).
Regarding claim 17, Klein teaches wherein said activation comprises induction of proliferation of regulatory T cells and/or induction of IL-2 receptor signaling in regulatory T cells (claim 51).
Regarding claim 18, Klein teaches a pharmaceutical composition comprising the fusion protein of any one of claims 1-29 or 34 and a pharmaceutically acceptable carrier (claim 35).
Regarding claims 1-2 and 4-5, Harris teaches a bispecific antibody that binds to IL-2RB/G heterodimeric receptor to preferentially promote in vivo expansion of CD8 and NK cells rather than Treg cells as promoted by native IL-2 (abstract and intro). Harris further teaches that due to its unique signaling properties, low dose rhIL-2 has been used in the clinic to stimulate T-regs to treat autoimmunity, while high-dose rhIL-2 was developed and approved for the treatment of cancer, but its short half-life and narrow therapeutic window have created significant challenges for the safe and effective use of rhIL-2 in patients (intro, para 2). Harris further teaches NGS antibody discovery used to identify novel, anti-IL-2Rβ and anti-IL-2Rγ monospecific UniAbs that could be combined into bispecific molecules capable of binding and activating the intermediate affinity IL-2Rβγ receptor (results para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to develop a trispecific VHH as taught by Pekar to target the components of the IL-2R as taught by Klein using heavy chain only unibodies as taught by Harris. The ordinary artisan would have been motivated to do so because Klein teaches there is a need for a new therapeutic approach that re-establishes the natural regulatory T cell (Treg) mediated dominant immune tolerance that can be achieved by preferentially targeting the IL-2RA/B/G over the intermediate receptor IL-2B/G. Pekar teaches that VHH-based IgG-like bi-and trispecific antibody platform appears to have the versatility to combine up to three preexisting VHHs in one multispecific molecule with the benefits of multiple formats and good protein expression yields. Harris teaches heavy chain only antibodies specific for anti-IL-2Rβ and anti-IL-2Rγ developed through NGS antibody discovery that can be reformatted into multispecific formats. The ordinary artisan has a reasonable expectation of success to generate a tri-specific antibody for IL-2RA, IL-2RB and IL-RG comprised of VHH domains that preferentially binds to the IL-2RA/B/G receptor to stimulate regulatory T cells for the treatment of autoimmune disease.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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