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 .
Status of Claims
Claims 1, 5-8, 12, 16, 19-21, 23-24, 26-27, 29, 42, 46, and 57 are amended. Claims 2-4, 9-11, 13-15, 17-18, 28, 30-41, 43-45, 47-51, and 53-56 are cancelled. Claims -----1, 5-8, 12, 16, 19-27, 29, 42, 46, 52 and 57 are currently pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The claims have an earliest effective filing date of 01/15/2021, corresponding to application China PCT/CN2021/072249.
Information Disclosure Statement
The Information Disclosure Statements filed on 07/14/2023 and 07/27/2025 have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Regarding claims -----1, 5-8, 12, 16, 19-24, 26, 27, 29, 42, 46, and 57, it is noted that claim 1 recites, for example, “a heavy chain variable region shown in SEQ ID NO: 25.” The recitation of a heavy chain variable region shown in SEQ ID NO: 25 includes partial sequences of SEQ ID NO: 25 that may comprise, for example, a single amino acid. As such one skilled in the art would be unable to readily delineate the metes and bounds of the claim. This issue may be remedied by amending claim to recite “the heavy chain variable region shown in SEQ ID NO: 25,” and making similar amendments to parts (b)-(f) of the claim.
Applicant is encouraged to make similar amendments to claim 5. For example “HCDR1 shown in SEQ ID NO: 7” should be amended to recite “the HCDR1 shown in SEQ ID NO: 7.”
Applicant is encouraged to make similar amendments to claims 6-8 and 20.
Regarding claims 29 and 46, the phrase "optionally" 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).
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, 6-7, 12, 16, 19-24, 26-27, 29, 42, 46, and 57 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Claim 1 is drawn to a binding domain, e.g. an antibody that binds TRPV6, wherein the binding domain comprises:
three heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 and three light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, and wherein the three heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 are included in the following heavy chain variable region: (a) a heavy chain variable region shown in SEQ ID NO: 25; (b) a heavy chain variable region shown in SEQ ID NO: 27; or (c) a heavy chain variable region shown in SEQ ID NO: 29, and the three light chain complementarity determining regions LCDRI, LCDR2 and LCDR3 are included in the following light chain variable region: (d) a light chain variable region shown in SEQ ID NO: 26; (e) a light chain variable region shown in SEQ ID NO: 28; or (f) a light chain variable region shown in SEQ ID NO: 30.
The claims encompass a large number of anti- TRPV6 antibodies having diverse heavy and light chain CDR amino acid sequences. Following a review of the specification, it appears that Applicant has disclosed three anti-TRPV6 trispecific binding domains, specifically, the CB-Anti-0001 antibody, which comprises the VH and VL of SEQ ID NO(s): 25 and 26, respectively, b) the CB-Anti-0002 antibody, which comprises the VH and VL of SEQ ID NO(s): 27 and 28, respectively, and c) the CB-Anti-0003 antibody, which comprises the VH and VL of SEQ ID NO(s): 29 and 30, respectively, see Table 2. However in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to encompass multiple anti-TRPV6 trispecific binding domains having diverse heavy and light chain CDR sequences. Even though Applicant has disclosed three species within said genus, the specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequences (and combinations of said CDR sequences) give rise to antibody molecules capable of binding TRPV6. As detailed below Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
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.
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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. In the instant case, Applicant has disclosed three species within the genus claimed. However given the substantial antibody structure variation within the genus, the disclosure of one species comprised within the claimed genus is not sufficiently representative of the entire genus.
Furthermore Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences (or combinations thereof) that confer upon an antibody the ability to bind TRPV6, because the instant specification does not provide structural antibody features that correlate with a functional ability to bind TRPV6. To elaborate on why the claimed antibodies lack adequate written description, Mariuzza (Annu. Rev. Biophys. Biophys. Chem., 16: 139-159, 1987) reviews the structural basis of antigen-antibody recognition and teach that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure that fully comprises six CDRs, three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of the antibody’s antigen-binding specificity. In view of Mariuzza, it is apparent that antibodies having less than all six CDRs that form the antigen binding site of a conventional antibody in their proper context of heavy and light chain variable domains do not describe the particularly identifying structural feature of the antibody that correlates with the antibody’s ability to bind antigen. Absent a description of the at least minimal structural features correlating with a functional ability to bind TRPV6 which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences (or combinations thereof) may be combined such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to bind TRPV6.
Furthermore while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example in a series of experiments involving a monoclonal antibody to Legionella pneumophilia serotype 1, McCarthy et al. (J. Immunol. Methods, 251(1-2): 137-149, 2001) demonstrated that a single VH CDR3 substitution of tyrosine to serine at position 95 resulted in the total loss of antigen recognition in an ELISA. Lin et al. (African Journal of Biotechnology, 10(79):18294-18302, 2011) teach that a single amino acid substitution in the VL CDR3 of an anti-avian infectious bronchitis virus (IBV) single-chain antibody (ZL.80) may abrogate binding. For example at Figure 3, Lin et al. demonstrate that replacing either the Cys105 or Asp106 residue in the VL CDR3 of ZL.80 with an alanine residue reduces binding to near negative control levels. Lin et al. also teach that some single amino acid substitutions in the VL CDR3 of ZL.80 may significantly improve binding. For example replacing the Val108 residue in the VL CDR3 of ZL.80 with a tyrosine residue results in a 12.9-fold increase in affinity compared to parental ZL.80. Accordingly absent empirical determination, one skilled in the art would be unable to predict or envision which VHs and VLs of claim 1 may be combined such that the resultant antigen-binding region residues form an antigen-binding site capable of binding TRPV6. 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, in the form of heavy and light chain CDR amino acid sequences, that correlate with the ability to bind TRPV6, and because the three disclosed species detailed above 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.
Although screening techniques can be used to determine which VHs and VLs of claim 1 may be combined such that the resultant antigen-binding site is capable of binding TRPV6, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
Accordingly given the unpredictability associated with antibody CDR region changes on antigen binding and given the lack of particularity with which the claimed antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed.
Claim 57 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Although the specification is enabled for treating cancer, the specification is not enabled for preventing cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include but are not limited to:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant to this rejection are 1) the amount of direction provided by the inventor and 2) the existence of working examples. In the instant case, the amount of direction provided by the inventor and existence of working examples disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue experimentation.
(1) The amount of direction provided by the inventor - The amount of guidance or direction needed to enable an invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004). Due to the high level of unpredictability in the area of disease prevention, particularly cancer prevention, the skilled artisan would need significant guidance in preventing cancer by practicing the claimed method. The skilled artisan recognizes that keeping individuals free of cancer indefinitely is an intractable proposition, if not now wholly impossible, given, for example, that cancers are widely heterogeneous diseases, having widely varying pathologies and etiologies, and with causes that are multifactorial and as yet only partially characterized and poorly understood. It is generally recognized that a disease cannot be prevented unless and until its causes are fully appreciated and understood to a degree that it becomes possible to intercede effectively to block its onset or development by any cause.
(2) The existence of working examples – The examples of the specification demonstrate methods that may be used to treat (cure or ameliorate) cancer; however there is no showing in the specification of any means by which one skilled in the art could prevent cancer. Therefore one skilled in the art would be subject to undue experimentation to practice the instant invention as it is currently claimed.
In conclusion upon careful consideration of the Wands factors that are used to determine whether undue experimentation is required to practice an invention, the amount of direction provided by the inventor and the working examples provided, as filed, is not deemed sufficient to enable the skilled artisan to make and/or use the invention commensurate in scope with the instant claims at the time the application was filed without undue experimentation.
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.
Claim 12 is 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. Claim 1 requires three HCDRs and three LCDRs; however claim 12 recites a dAb, which is known in the art as a domain antibody. Domain antibodies typically comprise either a VH or a VL and as such, only comprise three CDRs. As such claim 12 fails to limit the claim from which it depends. 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.
Claim Rejections - 35 USC § 103
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 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.
Claim(s) 52 is rejected under 35 U.S.C. 103 as being unpatentable over Galfre et al (Methods in Enzymology, Vol 73, 3_46, 1981; published 1981) in view of Wissenbach et al (WO0210382; published 02/07/2002).
Galfre et al teach a method for preparing antibodies comprising immunizing a mouse with an antigen, performing cell fusion, screening and cloning an immunopeptide to obtain a positive hybridoma cel line that secretes specific antibodies (Galfre et al, pg. 15, Figure 3).
Therefore, Galfre et al teach a method for preparing an antigen specific antibody. Galfre et al do not teach a method of preparing an antigen wherein the antigen specific antibody binds TRPV6. This deficiency is remedied by Wissenbach et al.
Wissenbach et al teach an amino acid sequence comprising 100% of instant SEQ ID NO: 3 (Wissenback, pg. 11-12, Figure 8A), the method of making a protein from the amino acid sequence, and the protein derived from the method, which would result in a TRPV6 protein.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Galfre et al with those of Wissenbach et al to arrive at a method of preparing an antibody specifically binding to TRPV6. One of ordinary skill would be motivated to do so, because Galfre et al teach a method for preparing antibodies comprising immunizing a mouse with an antigen, performing cell fusion, screening and cloning an immunopeptide to obtain a positive hybridoma cell line that secretes specific antibodies. Furthermore based upon the teachings of Wissenbach et al, one of ordinary skill in the art would have been motivated to create a TRPV6 antibody to treat cancer (Wissenbach, page 2-3, Background Section). As such one of ordinary skill in the art would have been motivated to modify the invention of Galfre et al to further include the immunization of the antibody producing mouse with the TRPV6 protein of Wissenbach et al, because there would have been a reasonable expectation of success that the resultant invention, which comprises a method of preparing an antibody specifically binding to TRPV6 comprising coupling the amino acid sequence shown in SEQ ID NO: 3 with a carrier protein to obtain TRPV6 antigen peptide; immunizing a mouse with the TRPV6 antigen peptide, performing cell fusion screening cloning and selection to obtain an antibody specifically binding to TRPV6, is effective in producing an anti-TRPV6 antibody that can treat cancer. The invention of Gafre et al and Wissenbach et al meets the limitations of claim 52.
Conclusion
Claim 25 is allowed.
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/J.K.D./Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642