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
Claim Status
Claims 1-14, 16-20 are currently pending. Claims 1-3 have been amended. Claim 15 is canceled. There are no new claims. Claims 1-14, 16-20 will be examined on the merits.
Election/Restrictions
Applicant’s election of species without traverse of the anti-CD 16A single-domain antibodies comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, where HCDR1 comprises the amino acid sequence of SEQ ID NO: 23, HCDR2 comprises the amino acid sequence of SEQ ID NO: 24, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 25 and SEQ ID NOs: 15-18 as in claim 9 in reply filed on March 5, 2026 is acknowledged.
Priority
Acknowledgement is made of applicant’s claim for foreign priority based on an application filed in Republic of China on January 27, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement (IDS)
The IDS submission is in compliance with the provisions of 37 CFR 1.97.
Objection
Claims 16, 19 are objected to because of the following informalities:
Claims 16, 19 recite “the individual is a mammal, or the individual is a human”. However, human is a mammal. The phrase is interpreted to mean “including human”.
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.
Claims 4-9, 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.
Claim 4-9 recites the term “optionally”. However, it is unclear which genus of monospecific antibody molecule is being claimed. Therefore, the scope of the claim is unclear in reference to “optionally”.
Claims 4 recites “the Fc region lacks or has reduced effector functions, or the Fc region has a LALA mutation”. However, it is unclear how the Fc region can either have reduced effector functions or not have effector functions at all. Also, it is unclear what is the effector function and wherein the LALA mutation is located within the Fc region sequence. Therefore, claim 4 is indefinite.
Claim 5 recites “an immunoglobulin Fc region located at the C-termini of the anti-CD16A single antibody and Fab fragment binding. However, it is unclear wherein the immunoglobulin Fc region fragment sequence is located within the C-terminal amino acid sequence of the anti-CD16A single antibody and Fab fragment binding. Also, it is unclear wherein the LALA mutation is located within the Fc region sequence. Therefore, claim 5 is indefinite.
Claims 6 recites “the immunoglobulin is an IgG1, IgG2, or IgG4 immunoglobulin, optionally, the immunoglobulin is an IgG1 immunoglobulin, or, the immunoglobulin is a human IgG1 immunoglobulin” However, it is unclear how the immunoglobulin can be any IgG1, IgG2, or IgG4 immunoglobulin. Also, it is not clear how IgG1 immunoglobulin can be any IgG1 and specifically, a human IgG1 immunoglobulin. Therefore, claim 6 is indefinite.
Claim 7 is rejected as lacking descriptive support as outlined for claim 4. Also, claim 7 recites “heavy chains of the antibody molecule each comprise a protuberance and a cavity in Fc domains thereof, and the protuberance or the cavity in the Fc domain of one heavy chain can be placed at the cavity or the protuberance in the Fc domain of the other heavy chain”. However, it is unclear wherein the protuberance and a cavity in Fc domains thereof and the protuberance or the cavity in the Fc domain of one heavy chain can be placed at the cavity or the protuberance in the Fc domain of the other heavy chain is located within the heavy chains sequence of the claimed monospecific antibody molecule. Therefore, claim 7 is indefinite.
Claim 8 is rejected as lacking descriptive support as outlined for claim 5.
Claim 9 is rejected as lacking descriptive support as outlined for claim 8.
Claim 13 recites “a nucleic acid encoding the anti-CD16A single-domain under conditions suitable for expression of the nucleic acid”. However, the recitation “suitable” is vague. Therefore, claim 13 is indefinite.
Claim 19 recites “a method for treating and/or preventing a disease in an individual”. However, it is unclear which disease can be treated and/or prevented by the method. Therefore, claim 19 is indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14, 18 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 14, 18 fail to further limit the subject matter of the claims from which they depend. The limitations in the claims recite the intended use of “a pharmaceutical composition” of claims 1, 4 and do not provide a further limit on claim 14, 18.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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 3-9, 13, 16-20 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 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.
Claims 1, 2 and any claim that depends directly or indirectly from 1 or 2 should be included in the rejection. Claims 1 and 2 don’t have description because only one chain is described.
The following quotation from section 2163 of the Manual of Patent Examination
Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
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... reduction to drawings...or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would
recognize from the specification the scope of what is being claimed.
Claim 3 recites an anti-CD16A single-domain antibody, comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 1 or a sequence having at least 90% identity thereto. The SEQ ID NO: 1 comprises 3 CDRs in an amino acid sequence of a heavy chain variable region set forth in claim 1.
In support of the claimed genus, the specification discloses “an anti-CD 16A single-domain antibody, comprising: (a) 3 CDRs in an amino acid sequence of a heavy chain variable region set forth in SEQ ID NO: 1; or a CDR variant having no more than 3, no more than 2, or no more than 1 amino acid residue replacement as compared to any one of the 3 CDRs”. See specification; page 3. Also, the specification discloses that preferably, the amino acids changes include substitutions, insertions, or deletions of amino acids. See page 18. Yet, the specification teaches that “a nucleic acid hybridized under a stringency condition with the following nucleic acid or a nucleic acid encoding a polypeptide sequence having one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions compared with the following nucleic acid: a nucleic acid encoding an amino acid sequence selected from any one of SEQ ID NOs: 1-4; or a nucleic acid encoding an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence selected from any one of SEQ ID NOs: 1-4”. See specifications; page 23.
However, it is not clear what underlies the suggested substitutions as the alternative embodiments were not reduced to practice to demonstrate that they maintain binding to the epitopes; no guidance it provided to the skilled artisan as to which substitutions to choose to incorporate. Further, the attempted consensus sequences, and potential alternative residue substitutions are not claimed; rather, the claim encompasses numerous potential substitutions beyond those described in the specifications. When determining the representative examples and the art, it is important to consider whether there is evidence of a singular shared structural feature which imparts the defining property of the claimed genus, and which would necessarily be present in every species of the claimed genus. The specifications do not teach the physical features (or amino acid residues encoding said features) which impart the property of binding the same epitope. Further, a description of the type and number of amino acid residue substitutions that may be made at such identified positions within the sequence, that result in “at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%” sequence identity to a selected sequence, would be essential in determining the degree of variability that may be allotted in total sequence identity. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants (variable domains with 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequences) would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims. Without the identification of the necessary shared structural properties of all species variants that fall within the scope of the genus, it may be that an embodiment species comprising an H3-CDR with < 90% in shared sequence identity to any of claimed sequences, would still bind the same epitope; or conversely, that antibodies with > 99% sequence identity, but comprising a deleterious mutation in the H3-CDR region would lose functional binding to an epitope. The claims encompass a sub-genus of variant embodiments which comprise unidentified variant CDR sequences; thus, under the broadest reasonable interpretation, claim 3 encompasses a genus of anti-CD16A polypeptides. anti-CD16A single-domain antibody.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. It is known in the art that the CDR regions are particularly sensitive to alterations, such that substitution of a single amino acid in a CDR region can alter, completely ablate, or even enhance binding the target antigen (Chen et al., 1992). Here the applicants disclose an amino acid sequence of a heavy chain variable region set forth in SEQ ID NO: 1 comprising the 3 CDRs with significantly variable amino acid sequences of HCDR1-3 beyond the shared, and broad, limitation described in claim 1. None of these embodiments demonstrate the shared structural properties that define the genus beyond the essential property of binding CD16A; specifically, those structural properties that impart the binding specificity of the anti-CD16A single-domain antibody.
Therefore, claim 3 is rejected for lack of adequate written description support.
Claims 4, 7 are rejected as lacking adequate descriptive support for possession of a genus of antibody comprising the anti-CD16A single-domain antibody and an immunoglobulin Fc region, wherein the Fc region lacks or has reduced effector functions, or the Fc region has a LALA mutation.
Claim 5 is rejected as lacking adequate descriptive support for possession of a genus of Multispecific antibody comprising the anti-CD16A single-domain antibody, a Fab fragment binding to a second antigen and an immunoglobulin Fc region located at the C-termini of the (i) and, wherein the Fc region lacks or has reduced effector functions, or the Fc region has a LALA mutation; wherein the multispecific antibody molecule is a bispecific antibody molecule.
Claim 8 is rejected as lacking adequate descriptive support for possession of a genus of multispecific antibodies, wherein the second antigen is selected from a tumor-associated antigen, a virus-associated antigen, and a bacteria-associated antigen, wherein optionally, the tumor- associated antigen is selected from, HER2, BCMA, MAGE, BAGE, MART, gp100, CD19, CD20, CD30, CD33, CD70, EpCAM, EGFR1, EGFR2, EGFR3, EGFR4, PLAP, PSMA, Claudin18.2, PD-L1, MUC1, and MUC16.
Claim 9 is rejected as lacking adequate descriptive support for possession of a genus of anti-CD16A bispecific antibodies that specifically binding HER2 or BCMA. Claim 9 recites the multispecific antibody molecule or the antigen-binding fragment according to claim 8, which is: i) an anti-CD16A/HER2 bispecific antibody or an antigen-binding fragment, comprising the anti-CD16Asingle-domain antibody and an antibody fragment specifically binding to HER2, wherein optionally, the antibody fragment specifically binding to HER2 comprises 3 CDRs in an amino acid sequence of a heavy chain variable region set forth in SEQ ID NO: 15; and 3 CDRs in an amino acid sequence of a light chain variable region set forth in SEQ ID NO: 16; or, the antibody fragment specifically binding to HER2 comprises 3 CDRs in an amino acid sequence of a heavy chain variable region set forth in SEQ ID NO: 15 and 3 CDRs in an amino acid sequence of a light chain variable region set forth in SEQ ID NO: 16; or, the antibody fragment specifically binding to HER2 comprises an amino acid sequence of a heavy chain variable region set forth in SEQ ID NO: 15 or a sequence having at least 90% identity thereto; and an amino acid sequence of a light chain variable region set forth in SEQ ID NO: 16 or a sequence having at least 90% identity thereto; or, ii) an anti-CD16A/BCMA bispecific antibody or an antigen-binding fragment, comprising the anti-CD16A single-domain antibody and an antibody fragment specifically binding to BCMA, wherein optionally, the antibody fragment specifically binding to BCMA comprises 3 CDRs in an amino acid sequence of a heavy chain variable region set forth in SEQ ID NO: 17; and 3 CDRs in an amino acid sequence of a light chain variable region set forth in SEQ ID NO: 18; or, the antibody fragment specifically binding to BCMA comprises 3 CDRs in an amino acid sequence of a heavy chain variable region set forth in SEQ ID NO: 17 and 3 CDRs in an amino acid sequence of a light chain variable region set forth in SEQ ID NO: 18; or, the antibody fragment specifically binding to BCMA comprises an amino acid sequence of a heavy chain variable region set forth in SEQ ID NO: 17 or a sequence having at least 90% identity thereto; and an amino acid sequence of a light chain variable region set forth in SEQ ID NO: 18 or a sequence having at least 90% identity thereto.
The claim is interpreted to encompass a significant number of variant peptides, comprising a sub-genus of variant embodiments which comprise unidentified variant CDR sequences; with no limitation as to which residues may be substituted, or with which amino acids, and wherein the substitutions may occur anywhere any of the CDR sequences; thus, under the broadest reasonable interpretation, claim 9 encompasses a genus of the bispecific antibodies, anti-CD16A/HER2 and anti-CD16A/BCMA. Therefore, claim 9 is rejected for lack of adequate written description support.
In support of the claimed genus, the specifications disclose that “an antibody that shows identical or similar binding affinity and/or specificity as a reference antibody refers to an antibody that is capable of having at least 50%, 60%, 70%, 80%, 90%, or 95% or more of the binding affinity and/or specificity of the reference antibody. This can be determined by any method known in the art for determining binding affinity and/or specificity”. Also, the specifications disclaim that the bispecific antibodies in Table 3, see page 37 and heavy chain antibodies in table 2 and the determination of epitope of human CD16A based on anti-CD16A heavy- chain antibodies, see example 4; page 33. The specification also teaches that a high-affinity single-domain antibody that specifically binds to human CD16A, does not bind to human CD16B, and cross-reacts with monkey CD16A, which is capable of performing construction and assembly of multispecific antibodies (e.g., bispecific antibodies) in different structural forms in free combination with different antibodies and antibody fragments against other antigens to maximize activation of NK cells and mobilize NK cells to mediate, for example, anti-tumor immunity; and overcoming problems of low tumor tissue permeability, strong immunogenicity, and the like, caused by overlarge molecular weight and steric hindrance of the conventional scFv or Fab. Therefore, in a first aspect, the present invention provides an isolated anti-CD 16A single-domain antibody, comprising (a) 3 CDRs in an amino acid sequence of a heavy chain variable region set forth in SEQ ID NO: 1; or a CDR variant having no more than 3, no more than 2, or no more than 1 amino acid residue replacement as compared to any one of the 3 CDRs. See specifications, page 3; Summary. “The amino acid changes described here include substitutions, insertions, or deletions of amino acids”. See page 18; lines 24-34. The specifications also teaches that “The present invention further provides a nucleic acid hybridized under a stringency condition with the following nucleic acid or a nucleic acid encoding a polypeptide sequence having one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions compared with the following nucleic acid: a nucleic acid encoding an amino acid sequence selected from any one of SEQ ID NOs: 1-4; or a nucleic acid encoding an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence selected from any one of SEQ ID NOs: 1-4. See page 23; lines 11-22. However, it is not clear what underlies the suggested substitutions as the alternative embodiments were not reduced to practice to demonstrate that they maintain binding to HER or BCMA; no guidance it provided to the skilled artisan as to which substitutions to choose to incorporate. Further, the potential alternative residue substitutions are not claimed; rather, the claim encompasses numerous potential substitutions beyond those described in the specifications. When determining the representative examples and the art, it is important to consider whether there is evidence of a singular shared structural feature which imparts the defining property of the claimed genus, and which would necessarily be present in every species of the claimed genus.
Further, a description of the type and number of amino acid residue substitutions that may be made at such identified positions within the sequence, that result in “at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%” sequence identity to a selected sequence, would be essential in determining the degree of variability that may be allotted in total sequence identity. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants (variable domains with 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical sequences) would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims. Without the identification of the necessary shared structural properties of all species variants that fall within the scope of the genus, it may be that an embodiment species comprising an H3-CDR with < 90% in shared sequence identity to any of claimed sequences, would still bind anti-CD16A; or conversely, that antibodies with > 99% sequence identity, but comprising a deleterious mutation in the H3-CDR region would lose functional binding to anti-CD16A. The claims encompass a sub-genus of variant embodiments which comprise unidentified variant CDR sequences; thus, under the broadest reasonable interpretation, claim 9 encompasses a genus of anti-CD16A polypeptides. Further, the “or” language separates the dependency of the VH and VL regions being combined. Thus, the VH and VL domains are highly promiscuous, and there is insufficient descriptive support for possession of a genus of VH and VL domains with at least 10% of amino acid substitutions or 90% sequence identity to the VL and VH domains of the isolated antibody or fragment thereof, which still maintains specificity for anti-CD16A. Furthermore, the “or” language separates the dependency of the VH and VL regions being combined. Thus, the VH and VL domains are highly promiscuous, and there is insufficient descriptive support for possession of a genus of VH and VL domains with at least 10% of amino acid substitutions or 90% sequence identity to the VL and VH domains of the isolated antibody or fragment thereof, which still maintains specificity for anti-CD16A.
However, it is apparent that the specification does not teach the full breath of genus, wherein an anti-CD16A/HER2 bispecific antibody or an antigen-binding fragment, comprising the anti-CD16Asingle-domain antibody and an antibody fragment specifically binding to HER2 sequences or an anti-CD16A/BCMA bispecific antibody or an antigen-binding fragment, comprising the anti-CD16A single-domain antibody and an antibody fragment specifically binding to BCMA of claim 9. The specification does not provide adequate descriptive support for all embodiments encompassed in the claim.
Thus, claim 9 is rejected for lack of adequate written description support.
Regarding the state of the art; it is known in the art that the antigen binding domain of an antibody requires the 6 complementarity determining regions (CDR) of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus, the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). However, the structure-to-function correlation continues to be highly unpredictable. For example, Chen et al., (1992) teaches that a single amino acid substitution in the VH CDR2 of PC-specific T15 antibody could increase, decrease or ablate binding the target antigen (abstract, Fig. 3), and this occurred in an unpredictable manner based on which residue was mutated. Similarly, a single point mutation in the heavy chain CDR3 region of the high affinity anti-VEGF antibody G6.31, could in some cases enhance, or otherwise completely ablate binding to the target antigen, and this also occurred in an unpredictable manner (Koenig et al., PNAS, 2017). That is, only screening each mutation individually provided insight as to the resulting changes in functionality. In some cases, this extends even beyond the CDRs. Within the framework regions, Koenig et al. (PNAS, 2017) teaches that various amino acid point mutations can increase or decrease binding or neutralization capacity. Some amino acid residues are more tolerant to substitution, while other “conserved” residues are less tolerant, such that a single amino acid substitution may defunctionalize the antibody (pg. E487, Figure 1). Further, it is known that the heavy chain CDR2 and CDR3 regions contain most of the residues that have a major contribution to the binding free energy of the antigen binding domain (Dondelinger et al., 2018; page 8, column 1, paragraph 2 – column 2, paragraph 1). Regarding single domain antibodies (sdAbs), which comprise only a VHH heavy chain, comprising the 3 heavy chain CDRs, Sheriff et al., (1996) teaches that while the usual conception is that an antibody (or receptor) envelops its ligand, with sdAbs derived from camels, the antibody inserts a part of its binding surface deeply into a pocket on the surface of the ligand; and that about 70% of the total surface area buried in this interaction is contributed by CDR3 (page. 735, column 2, paragraph 2 – column 3, paragraph 1). Thus, the CDR3 of sdAbs is of considerable importance to the functionality of the sdAb with regard to specificity and affinity.
Thus, the hyper-variable regions, comprising the complementary set of CDRs, are well established in the art as the portion of the binding regions which impart the specificity of the antibody; and yet, there is no way to look at an amino acid sequence and envision, a priori, whether the combination of CDRs will bind a particular epitope, even when the CDRs are highly related, without teachings of the basic shared amino acid residues that are sufficient to impart functional binding across all variants. Further, even when provided with several related antibodies that bind the desired target, this does not represent the potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg. 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg. 11). Thus, when claiming a genus of antibodies, or antigen binding polypeptides, based on their binding to a common target, the representative examples must cover the full scope of structural variabilities which encompass all species variants that would bind the target.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants do not provide any variants of the claimed embodiments, in which alternative mutations were made, which were reduced to practice; nor do they identify the shared structural properties of the variants, such as the CDR residues or humanized framework regions, that would define the genus beyond the desired functionality.
Thus, one of skill in the art would not readily recognize the use of one genus of antibodies claimed by the applicant if there is lack of written description of the ability of the genus to bind antigen-binding fragment. The written description requirement is not fulfilled by the applicant. The written description requirement is not fulfilled by the applicant.
“The 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. Otherwise, the “claims 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- leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making 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 by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Therefore, neither the art nor the specification provide the full antibodies genus that can be bound to anti-CD16A single-domain and anti-CD16A bispecific antibodies (multispecific antibodies) as claimed by the invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
In view of this uncertainty and the lack of a representative number of examples of the claimed genus, the claims 3-9, 13, 16-20 are rejected for lack of adequate written description support.
In order to comply with the written description requirement, the applicant must fully disclosure the full genus of antibodies to bind anti-CD16A single-domain antibodies and bispecific anti-CD16A HER2/BCMA antibodies by the applicant’s invention in the specifications.
Claims 17, 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 47 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
Claims 17, 20 rejected as lacking adequate descriptive support for the method of treating and/or preventing a disease in an individual, the method comprising administering to the individual the anti-CD 16A single-domain antibody according to claim 1, wherein optionally, the individual is a mammal, or, the individual is a human. The claims broadly encompass forms/types of cancer however, the specification does not teach the treatment of all the forms/types of cancers said to be preventable and/or treatable by the applicant’s method. The applicability of method to all types/forms of cancers asserted in the claims mentioned above is unknown and/or not readily reproducible by the artesian.
The specification teaches that “through extensive and intensive studies and extensive screening, the inventors have succeeded in obtaining a high-affinity single-domain antibody (sdAb) that specifically binds to human CD 16A, does not bind to human CD16B, and cross-reacts with monkey CD16A. Experimental results show that the single-domain antibody can specifically bind to human CD16A, does not bind to human CD16B, and cross-reacts with monkey CD16A; meanwhile, it has relatively high binding affinity, small molecular weight and good stability, has strong antigen-specific activation of human NK cells and tumor inhibitory effect, and thus is an ideal single-domain antibody for construction of bispecific antibodies or NK cell engagers and research and development of anti-tumor active drugs. Therefore, the present invention provides a high-affinity single-domain antibody that specifically binds to human CD16A, does not bind to human CD16B, and cross-reacts with monkey CD16A, which has the following properties: 1) capable of performing construction and assembly of multispecific antibodies (e.g., bispecific antibodies) in different structural forms in free combination with different antibodies and antibody fragments against other antigens to maximize activation of NK cells and mobilize NK cells to mediate, for example, anti-tumor immunity; and 2) overcoming problems of low tumor tissue permeability, strong immunogenicity, and the like, caused by overlarge molecular weight and steric hindrance of the conventional scFv or Fab”. See specification; page 3. It is apparent that the specification teaches the effect of the claimed antibodies in cells from human donors and the potentially use of these antibodies for treating forms of cancer, however, does not teach the claimed method is capable of preventing and/or treating all types/forms of cancers claimed in the invention. Thus, there is also uncertainty regarding to the use of the method for the form of cancer mentioned above. Further, there is no teachings in the specification showing that the method can prevent and/or treat cancer in mammal subjects, including humans.
Thus, one of skill in the art would not readily recognize the use of the method to prevent and/or treat all types/forms of cancers claimed by the applicant if there is a lack of written description of method and use of the genus (types/forms of cancer) in the claims. The written description requirement is not fulfilled by the applicant.
In order to comply with the written description requirement, the applicant must fully disclosure all forms of cancers claimed to be preventable and/or treatable by the applicant’s invention regarding the protocol of use of the method for all forms/types of cancer in specifications.
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 by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. In the specification, there is no clear disclosure of each form/type of cancers have been prevented and/ or treated using the method claimed in the invention. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim 9 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wilson et al. (US. Pat. 10780182 B2; hereafter Wilson; PTO-892), and alternatively by Zhou et al. (US20200246381A1; hereafter Zhou; PTO-892).
As claim 9, Wilson teaches that the antibody sequences, SEQ ID NO: 2, 4 are 100% identical to SEQ ID NOs: 15, 16, respectively. See Figures below.
As claim 9, Zhou teaches that the antibody sequences, SEQ ID NO: 7 is 95.2% identical to SEQ ID NO: 17 and SEQ ID NO: 43 is 100% identical to SEQ ID NO: 18. See Figures below.
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Allowable subject matter
The anti-CD16A single-domain antibody comprising 3 CDRs in an amino acid sequence of a heavy chain variable region (VH) set forth in SEQ ID: 1 of claim 1 has been searched. However, it was not found any other sequence 100% identical to the antibody sequence of claim 1.
The HCDR1 set forth in SEQ ID NO: 23, HCDR2 set forth in SEQ ID NO: 24, and HCDR3 set forth in SEQ ID NO: 25 of claim 2 have been searched as well. However, it was not found any other HCDR sequence 100% identical to SEQ ID NOs: 23-25 to the HCD sequences of the antibody of claim 2.
Therefore, claims 1-2 are free of the prior art. Claims 10-12 are dependent of claim 1. Claims 1-2, 10-12 are allowable because no prior art was found for the antibody of claim 1-2, and dependent claims 10-12.
Conclusion
Claims 1-2, 10-12 are allowed. Claims 1, 2, 10-12
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PRICILA HAUK TEODORO whose telephone number is (571) 272-2784. The examiner can normally be reached M-F 6:15 AM-3:00 PM.
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/PRICILA NMN HAUK TEODORO/ Examiner, Art Unit 1645
/HEATHER CALAMITA/ Supervisory Patent Examiner, Art Unit 1684
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