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
Claims 34-37 and 53-71 are pending.
Claims 34-37 and 53-71 are under examination on the merits.
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. Claims 34-37 and 53-71 have an effective filing date of 07/06/2017, corresponding to EP17180064.2.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/07/2022 and 12/22/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections
35 U.S.C. 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 58, 60, and 61-66 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 58, the term “preferably” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 60 recites the trademarks/tradename Biacore. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify a means of performing surface plasmon resonance; however the recitation of trademarks/tradenames renders the claim indefinite.
Regarding claims 61-66, the phrase “in particular” 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).
35 U.S.C. 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 34-37 and 53-71 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.
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 34 is drawn to an antibody or a variant of said antibody that maintains the binding specificity of the antibody, wherein said antibody comprises a variable domain that binds to a protein of the CD28 family, such as PD-1, and a variable domain that binds to a protein of the B7 family, such as PD-L1, wherein the binding of the variable domain that binds to the extracellular region of PD-1 blocks the binding of PD-1 to PD-L1 and/or the binding of the variable domain that binds to the extracellular region of PD-L1 blocks the binding of PD-L1 to PD-1. Applicant has disclosed various heavy chain variable regions (VHs) that are comprised within anti-PD-1 antibodies, see, for example, claim 63, as well as various VHs that are comprised within anti-PD-L1 antibodies, see, for example, claim 66. Claim 67 recites a common light chain variable region (VL, SEQ ID NO: 6); however it is not clear from the specification whether the VL in claim 67 may be paired with the disclosed anti-PD-1 and anti-PD-L1 VH regions to yield functional antigen-binding regions. Even if it were clear from the specification that the VL in claim 67 may be paired with the disclosed anti-PD-1 and anti-PD-L1 VH regions to yield functional antigen-binding regions, claim 34 is drawn to a genus of antibodies or a variant of said antibody that maintains the binding specificity of the antibody, and absent empirical determination, one skilled in the art would be unable to determine whether a particular variant of an antibody, which encompasses antibody variants with substitutions, insertions, or deletions in the complementarity determining regions (CDRs), maintains the ability to bind antigen.
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 not described any variants of an antigen-binding regions that bind a protein of the CD28 family, such as PD-1, or a protein of the B7 family, such as PD-L1. As such the specification has not adequately described a representative number of species comprised within the claimed genus. The specification also fails to provide relevant, identifying characteristics for the genus of antibody variants claimed. This issue may be remedied by removing the recitation of “a variant of said antibody that maintains the binding specificity of the antibody.”
Further at issue with claim 34 is the recitation of a variable domain that can bind to a protein of the CD28 family and a variable domain that can bind to a protein of the B7 family. This recitation encompasses a) traditional antigen-binding domains that comprise a VH and a VL as well as b) single-domain antibodies, which are single monomeric antibody variable domains that are capable of binding antigen, see, for example, p. 67 and 68 of the specification. The specification does not disclose any particular single-domain antibodies which bind a protein of the CD28 family or a protein of the B7 family. Single-domain antibodies are distinct from traditional antibodies in that single-domain antibodies typically comprise less than six heavy and light chain CDRs, and the preparation of single-domain antibodies often involves the use of laboratory screening techniques, such as the immunization of camelids followed by phage display selection, see p. 1720 of Kijanka et al. (Eur J Nucl Med Mol Imaging, 40: 1718-1729, 2013, in IDS from 12/07/2022). It is therefore submitted that in the absence of empirical determination, one skilled in the art would be unable to readily envision at least most of the members comprised within the genus of single-domain antibodies which bind a protein of the CD28 family or a protein of the B7 family. As indicated above, 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. In the instant case, Applicant has not disclosed any species within the genus of single-domain antibodies which bind a protein of the CD28 family or a protein of the B7 family, and therefore a representative number of species have not been adequately described. The specification further fails to disclose relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the genus of single-domain antibodies which bind a protein of the CD28 family or a protein of the B7 family. Accordingly given the high level of unpredictability in the art and given the lack of particularity with which single-domain antibodies which bind a protein of the CD28 family or a protein of the B7 family 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 of single-domain antibodies which bind a protein of the CD28 family or a protein of the B7 family, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of single-domain antibodies which bind a protein of the CD28 family or a protein of the B7 family at the time the application was filed.
Claims 54-57 are drawn to an antibody that comprises a variable domain that binds to a protein of the CD28 family, such as PD-1, and a variable domain that binds to a protein of the B7 family, such as PD-L1, wherein the binding of the variable domain that binds to PD-1 blocks the binding of PD-1 to PD-L1, wherein the binding of the variable domain that binds to PD-L1 blocks the binding of PD-L1 to PD-1, wherein the binding of the variable domain that binds PD-1 blocks the binding of PD-1 to PD-L2, wherein the binding of the variable domain that binds PD-L1 blocks the binding of PD-L1 to CD80, and wherein, for example, said antibody is able to activate T cells in an antigen-specific CD4+ T cell assay more strongly than benchmark antibody 5C4 or benchmark antibody YW243.55.S70 or a combination of benchmark antibodies 5C4 and YW243.55.870; and/or that has a stronger CD4+ T cell activation potential in a mixed lymphocyte reaction (MLR) assay as compared to benchmark antibody 5C4 or benchmark antibody YW243.55.S870. Absent empirical determination one skilled in the art would be unable to readily identify which anti-PD-1 antibodies are capable of blocking the binding of PD-1 to PD-L1 or PD-L2 or which anti-PD-L1 antibodies are capable of blocking the binding of PD-L1 to PD-1 or CD80. Furthermore one skilled in the art would appreciate that different combinations of anti-PD-1 and anti-PD-L1 antigen-binding regions will demonstrate a range of T cell activation potential. While some anti-PD-1 and anti-PD-L1 antigen-binding region combinations would be expected to strongly activate T cells, other combinations would be expected to demonstrate poor T cell activation potential. Absent empirical determination one skilled in the art would be unable to readily envision whether a particular anti-PD-1 and anti-PD-L1 antigen-binding region combination is capable of demonstrating improved T cell activation when compared to the benchmark antibodies 5C4 and YW243.55.S870.
Claim 58 is drawn to an antibody that binds PD-L1 and has a binding affinity for an extracellular part of PD-L1 with an equilibrium dissociation constant (KD) of lower than or equal to 4.27 nM, preferably of lower than or equal to 1.31 nM, preferably of lower than or equal to 1.27 nM, as measured by SPR. One skilled in the art would appreciate that different anti-PD-L1 antigen-binding regions will demonstrate a range of KD values, and absent empirical determination one skilled in the art would be unable to readily envision whether a particular anti-PD-L1 antigen-binding region has a KD in the claimed range.
Claim 59 is drawn to an antibody that binds, for example, PD-1 or PD-L1, and is capable of enhancing the proliferation of CD4+ and/or CD8+ tumor-infiltrating T cells; or is capable of inducing a stronger T cell mediated anti-tumor response in vivo as compared to a combination of benchmark antibodies MK-3475 and YW243.55.S70. Absent empirical determination one skilled in the art would be unable to readily envision which anti-PD-1 or anti-PD-L1 antibodies are capable of enhancing the proliferation of CD4+ and/or CD8+ tumor-infiltrating T cells or are capable of inducing a stronger T cell mediated anti-tumor response in vivo as compared to a combination of benchmark antibodies MK-3475 and YW243.55.S70.
Claim 60 is drawn to an antibody that comprises a variable domain that binds to a protein of the CD28 family, such as PD-1, and a variable domain that binds to a protein of the B7 family, such as PD-L1, wherein the variable domain that binds an extracellular part of PD-1 is defined as a variable domain that when in a bivalent monospecific antibody format that comprises two of said variable domains that bind PD-1, inhibits PD-1/PD-L1 mediated inhibition of T cell receptor mediated activation of a Jurkat cell in a range of 20-150% when compared to the inhibition obtained with the antibody Nivolumab on a Jurkat cell; and/or wherein the variable domain that binds an extracellular part of PD-L1 is defined as a variable domain that when in a bispecific antibody that has a second variable domain that binds an irrelevant antigen such as Tetanus Toxoid, provides the bispecific antibody with a Kd of 0.1-14 nM for PD-L1 binding (as measured by Biacore). Absent empirical determination one skilled in the art would be unable to readily envision whether a particular anti-PD-1 antigen-binding region and anti-PD-L1 antigen-binding region meet the functional limitations of the claimed anti-PD-1 and anti-PD-L1 variable domains.
Claims 61-63 recite an antibody capable of binding to PD-1, wherein said antibody comprises a variable domain that binds to PD-1, wherein said variable domain comprises a VH (or CDRs comprised within said VH) from one of various recited VHs (MF6076, MF6236,…). One skilled in the art would be unable to readily envision the amino acid sequences of VL regions that could be paired with the recited VHs such that the resultant VH/VL pair forms an antigen-binding site capable of binding PD-1. Claims 64-66 recite an antibody capable of binding to PD-L1, wherein said antibody comprises a variable domain that binds to PD-L1, wherein said variable domain comprises a VH (or CDRs comprised within said VH) from one of various recited VHs (MF5359, MF5361,…). One skilled in the art would be unable to readily envision the amino acid sequences of VL regions that could be paired with the recited VHs such that the resultant VH/VL pair forms an antigen-binding site capable of binding PD-L1. It is noted that the specification does not disclose relevant, identifying characteristics of heavy chain CDR region amino acid sequences (or combinations thereof) that confer upon an antibody the ability to bind PD-1 (or PD-L1), because the instant specification does not provide structural antibody features that correlate with a functional ability to bind PD-1 (or PD-L1). To elaborate on why the claimed antibodies lack adequate written description, Mariuzza (Annu. Rev. Biophys. Biophys. Chem., 16: 139-159, 1987, in IDS from 12/07/2022) 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 PD-1 (or PD-L1) 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 chain variable region CDR amino acid sequences (or combinations thereof) may be combined such that a resultant heavy chain variable region comprises three CDRs that confer the ability to bind PD-1 (or PD-L1).
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, in IDS from 12/07/2022) 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, in IDS from 12/07/2022) 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 CDR residues comprised within the recited VHs could be changed such that the resultant variant CDR residues form an antigen-binding site capable of binding PD-1 (or PD-L1). 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 chain CDR amino acid sequences, that correlate with the ability to bind PD-1 (or PD-L1), it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met for claims 61-66.
Claims 67 and 68 are included in this rejection, because absent empirical determination, one skilled in the art would be unable to readily envision which heavy chain variable region sequences may be paired with the light chain variable regions of claims 67 and 68 such that a resultant antigen-binding domain is capable of binding PD-1 (or PD-L1).
Although screening techniques can be used to isolate heavy chain CDR variant antibodies that possess the ability to bind PD-1 (or PD-L1), 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.”
Applicant is informed that one potential means of overcoming the rejection of the claims under 35 U.S.C. 112(a) is by amending claim 1 to recite a) specific antigen-binding domains that bind the extracellular part of a protein of the CD28 family, wherein each antigen-binding domain comprises three distinct heavy chain CDRs and three distinct light chain CDRs, and b) specific antigen-binding domains that bind the extracellular part of a protein of the B7 family, wherein each antigen-binding domain comprises three distinct heavy chain CDRs and three distinct light chain CDRs.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642