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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(a)-(d) or (f), 365(a) or (b), or 386(a) is acknowledged. The application is the national stage entry of PCT/CN2022/114642, which claims foreign priority to PCT/CN2021/114549, filed August 25, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted December 3, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Claim Status
Claims 1, 3-7, 10-20, and 22-24 are under consideration in this office action.
Claim Objections
Claims 1, 4, 7, and 12 are objected to because of the following informalities:
Claims 1 and 4 use acronyms without first defining what they represent in the independent claims (see for example, “CDR1”, “CDR2”, “CDR3”, VHH). While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym.
In line 4 of claim 12, there is a comma and space missing in “5253”.
Claims 7 and 12 are directed to the same product, an antibody comprising a monomeric variable domain selected from the group consisting of SEQ ID NOs: 44, 47, 1, 5, 13, 17, 25, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, and 62. Applicant is advised that should claim 7 be found allowable, claim 12 will be objected to under 37 CFR1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP 608.01(m).
Appropriate correction is required.
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.
Claims 1, 3-7, 10, 14-20, and 22-24 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.
The term “about” in claim 1 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 3-7, 10, 14-20, and 22-24 are included in this rejection for being dependent on a rejected base claim and for failing to cure the indefiniteness.
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, 3-7, 10-20, and 22-24 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.
“[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.
Claim 5 recites the limitation wherein the antibody is “human”; in the specification, “human antibody” is not defined. “Humanized antibody” is defined as an antibody from non-human species whose protein sequences have been modified to increased similarity to antibody variants produced naturally in humans (specification from 2/9/2024, pg 9). While humanized antibodies are an example of a human intervention, human antibodies are a natural product because the intervention is only isolation, which does not significantly change or manipulate the naturally occurring product. The specification does not clearly set forth what “human antibody” means and how “human” antibodies are made and isolated; thus, “human” is interpreted to mean an antibody isolated from a human. Claim 5 fails to meet the written description requirement because the disclosure fails to describe clearly these human antibodies or show that the inventor was in possession of the human antibodies at the time the invention was filed. Therefore, the limitation of claim 5 directed to a human antibody must be cancelled from the claim.
Claims 1 and 3-6, 10, 14-15 are broadly drawn to isolated antibodies, or an antigen-binding portion thereof, comprising a monomeric variable domain comprising CDR1, CDR2, and CDR3 amino acid sequences, each CDR comprising up to about 3 amino acid substitutions. As such, these antibodies have variation within the CDR regions that define the antigen binding site of the antibody.
Claims 6 and 10 are directed to antibodies comprised of amino acid sequences that are more than 80%, 85%, 90%, 92%, 94%, 95%, 96%, 97%, 908%, or 99% identical to specific sequences set forth in claim 1; by virtue of the percent identity language, these claims encompass variants that do not require all three CDRs from a particular parental single domain antibody (sdAb).
Claims 1, 3, 5-7, and 10-15 are drawn to antibodies or antigen-binding portion thereof comprising a monomeric variable domain. According to the specification, “CH16a binding protein include chimeric, humanized and human antibodies (e.g., comprising 2 heavy and light chains)” [0039]. As such, the claims are directed to antibodies comprised of heavy and light chains, but the light chain variable region and the CDRs therein are left undefined.
Claims 16-20 and 22-24 are included in the rejection of the claims under 35 U.S.C. 112(a), because if one skilled in the art could envision the antibodies or antigen-binding portions thereof, absent empirical determination, one skilled in the art would be unable to envision which of said antigen-binding domains also meet the structural and functional limitations of claims 16-20 and 22-24.
As detailed below, applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus of claims 1, 3-7, 10-20, and 22-24, and as such, applicant’s disclosure does not satisfy the written description requirement of 30 U.S.C. 112(a).
As is well-known in the antibody art, the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level even when the same antigen is bound (see Edwards et al, abstract, instant PTO-892). It is also well established that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs that provide the majority of the contact residues for the binding of the antibody to its target epitope (see Almagro & Fransson, section 3 and figure 1, instant PTO-892).
While most antibodies utilize a VH+VL pair to form their antigen-binding site, examples of antigen binding domains comprising only a VH that in turn comprise only three CDRs also exist, often derived from camelids (see Muylderman, figure 2 and “Structure of the VHH”, instant PTO-892). But these single domain antibodies still utilize highly variable amino acid sequences to contact antigen, and their CDRs are likewise formed by the same type of genetic recombination event between V-D-J gene segments. Accordingly, the skilled artisan recognizes that it is also the case for a sdAb that, for it to be reasonably predictable, a variant would bind the same antigen as the parental sequence and that the conserved structure provided by the combination of the three CDRs in the context of appropriate framework sequences is generally still essential. Given the unpredictable effect on functional activity when residues in the CDRs are changed or not conserved between a parent and variant sequence, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, which sdAb variant sequences would retain antigen binding and other desired properties unless, at a minimum, they contained a set of three CDRs that had been experimentally demonstrated to confer antigen binding.
For claims drawn 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, 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). A sdAb described by a functional characteristic, such as an sdAb that binds CD16a, with up to 9 variants of the CDRs, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995).
The art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. See Chen et al., 1995 (instant PTO-892), which demonstrates single amino acid substitution in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody (see abstract). Also see Kussie (instant PTO-892), who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-azophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (see abstract).
Koenig 2017 (instant PTO-892) provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. Looking at figure 1, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning a complete loss of binding ability. In VH-CDR2, for example, mutating any given residue to cysteine, which is encompassed by the instant claims, resulted in reduced binding at 12 residues and a complete loss of binding at 5 residues. That is, at 100% of the positions, mutation to cysteine is reduced or ablated the antibody’s ability to bind the target. Looking at a specific position, in 100% of the mutations of residue 55, binding was reduced (15/19) or eliminated (4/19). While residues 56-65 appear more tolerant of change, residues 50-55 are generally intolerant of change (see abstract).
It is appreciated that Koenig is studying one specific antibody and there is no evidence that the instant sdAbs would react in the same way. However, this is part of the problem. It is entirely unclear from the specification which residues of applicant’s CDRs are tolerant or intolerant to change, and whether those tolerant positions are only tolerant to conservative mutations. The fact that some residues might tolerate mutation does not convey to the skilled artisan that applicant knew which of the claimed residues were tolerant of such, i.e. does not convey that applicant was in possession of those sequences which are mutated yet preserve the claimed function. In other words, the specification fails to convey possession of an invention commensurate in scope with what is now claimed and therefore fails to meet the written description requirement. Looking at Koenig figure 2A, ~200 mutations in the CDR region of the VH chain completely abrogates any binding. While 2B appears to indicate that the CDRs of VL are more tolerant of change than the heavy chain CDRs, still over half of the mutations reduce binding compared to the parent.
Making changes to the CDR sequence of an antibody/sdAb is a highly unpredictable process, and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions. Without this guidance or direction, the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Moreover, CDRs are not generally recognized as interchangeable, such that using one CDR from one antibody would not be reasonably expected to confer the same binding properties or even the same binding target when combined with two to five CDRs from other antibodies. For example, WO 2008068048 (instant PTO-892) discloses an antibody with a heavy chain comprising three CDRs (SEQ ID NO: 2) that binds secreted aspartyl protease from Candida sp. US 20170355756 (instant PTO-892) describes the same three CDRs in the heavy chain (C10-VH3) combined with a different light chain that binds human TDP-43. There is no evidence in the instant specification that the claimed sdAb is correlated to the required function when combined with any other light chain to form an antibody. As such, the specification fails to set forth a structure-function correlation sufficient to claim all possible antibodies defined comprised of the sdAb. The disclosure of 7 sdAb sequences of CDR1-3 does not convey possession of other antibodies with the same binding properties; possession of the precisely defined sequence of six CDRs for the antibody is required.
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only 7 species within the genus.
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible sdAbs that bind the disclosed antigen. The specification does not provide a consistent structure for all of the possible sdAbs and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
The specification discloses at least 7 sequences of anti-CD16a sdAb. However, as discussed above, without a way to determine how broad the genus of such sdAbs is, one cannot determine if these sdAbs represent the full breadth of what is claimed. The disclosure of these specific sdAbs would not convey to the artisan that applicant was in possession of the full genus of all antibodies with amino acid substitutions in the CDRs that possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
With the exception of specifically disclosed sdAbs with specific CDRs, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed sdAbs, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 1, 3-7, 10-20, and 22-24 do not meet the written description requirement.
Scope of Enablement
Claims 22-23 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 a method of promoting NK cell proliferation with the single domain antibodies of CDR1-3 of claim 1 with no amino acid substitutions, does not reasonably provide enablement for the treatment of cancer disease. 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 the invention commensurate in scope with these claims.
Case law holds that applicant’s specification must be “commensurately enabling [regarding the scope of the claims].” See Ex Parte Kung, 17 USPQ2d 1545, 1547 (Bd. Pat. Appl. Inter. 1989). Otherwise undue experimentation would be involved in determining how to practice and use applicant’s invention. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described in In re Colianni, 195 USPQ 150 (CCPA 1977) and have been adopted by the Board of Patent Appeals and Interferences in Ex Parte Forman, 230 USPQ 546 (BPAI 1986). Among these factors are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the breath of the claims,
5. the amount of direction or guidance present, and
6. the presence or absence of working examples.
The following is an analysis of these factors in relationship to this application.
Nature of the invention/breadth of claims
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the methods of claims 22-23 is that administration of anti-CD16a antibodies of claim 1 is a treatment for cancer. The claims read on all cancer types.
State of the art/predictability
The invention is related to novel anti-CD16a sdAbs and methods of promoting NK cell proliferation and treating cancer. CD16a (FcgRIIIA) is expressed on NK cells, and binding of the Fc portion of IgG1 antibodies to CD16a triggers NK cell proliferation and expansion (see Pahl et al, abstract and pg 517; instant PTO-892).
Antibodies that bind CD16a in an Fc-dependent manner can activate NK cells, and bispecific antibodies engineered to bind cancer antigens (e.g., CD30) and CD16a demonstrate amplified NK cell proliferation and expansion and enhanced cytotoxicity (Pahl et al, pg 518, column 1). The art at the time the instant application was filed provided enabling guidance for the use of bispecific antibodies that engage NK cells by targeting CD16a for cancer immunotherapy, as NK cells are potent in killing tumor cells (Zhao et al, instant PTO-892). However, there is no evidence that administration of an CD16a activator alone is sufficient to treat cancer.
Guidance/working examples
The applicant has demonstrated that the 7 sdAbs of instant claim 1 (the sdAbs without any amino acid substitutions) bind to CD16a (Figure 1). sdAb comprised of SEQ ID NOs: 2-4 and SEQ ID NOs: 6-8 exhibited ADCC activity in an assay (Figure 12), consistent with use of the claimed antibodies in a method of promoting NK cell proliferation. The in vivo anti-tumor activity of these sdAbs was not assessed.
Although the specification is enabling for a method of promoting NK cell proliferation, as evidenced by increase cytotoxicity in vitro, the enabling disclosure does not extend to a method of treating cancer, as required by instant claims 22-23. In the absence of a more specific therapeutic, it is unclear what types of cancer these sdAbs could be used to treat.
The instant specification is not enabling for claims 22-23 because one cannot follow the guidance presented therein, or within the art at the time of filing, and predictably practice the claimed method without engaging in extensive and undue experimentation. Given that the nature of the invention is in vivo treatment of cancer, a person having ordinary skill in the art would have to perform multiple further in vivo experiments, in animals and/or human subjects, in order to demonstrate whether the invention could or could not be used. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation for treating any disorder related to cancer or immune-related disease.
Therefore, in light of the above factors, it is seen that undue experimentation would be necessary for methods of treating cancer, and claims 22-23 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571)272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
Prosecution Insights