Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
Claims 1, 3, 5, 20-23, 25-26, 29, 31, 39, 45-46, 48-50, and 52-54 are pending and examined on the merits herein.
Specification
The use of the terms affibodies™, DARpins™, and nanobodies™ which are trade names or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 31 is 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 31 recites wherein the polypeptide is conjugated to a heterologous moiety, The use of the term “heterologous moiety” renders this claim indefinite. The instant specification discloses: In some embodiments, the heterologous moiety is a therapeutic agent, a diagnostic agent or a combination thereof. In some embodiments, the heterologous moiety is polyethylene glycol (PEG), hexadecanoic acid, hydrogels, nanoparticles, multimerization domains and carrier peptides (para 00150). The definition of moiety is a part or functional group. The general definition and instant disclosure do not render a clear definition of would and would not be considered a “heterologous moiety”.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 21-23, 25-26, 29, 31, 39, 45-46, 48-50, and 52-54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The teachings of the specification and the claimed invention:
Claim 1 is drawn to a genus of polypeptides comprising a VH and VL that binds to PCSK9 with at least 95% sequence identity to SEQ ID NO: 3 and 16 respectively.
Claims 3, 21-23, 25-26, 29, 31, 39, 45-46, 48-50, and 52-54 depend from claim 1 without rectifying the issue identified above and are therefore included in this rejection.
Claim 3 is further drawn to a genus of antibodies that bind to PCSK9 comprising a paratope that is identical to one of the eleven VH/VL pairs recited in the claim.
Claim 39 is further drawn to an option of an antibody that competes with the “Reference antibody” for binding to PCSK9
The instant specification discloses generation of 179 variants of the “Reference Antibody” which were categorized into computational design groups and wherein sequence variation was restricted to CDR regions and non-germline framework residues with a maximum of 14 mutations from the “Reference Antibody” (para 00251).
Variants were evaluated for improvements in developability, decreased immunogenicity, binding to PCSK9, disruption of PCSK9/ LDLR binding and internalization and self-association (para 00251). The instant specification further discloses that 63 variants bound PCSK9 and only 10 of those exhibited functional activity to disrupt PCSK9/LDLR (para 00252-3).
Regarding the Reference Antibody, the instant disclosure teaches that the reference polypeptide is an antibody, referred to herein as "the Reference Antibody," which comprises a VH region comprising the amino acid sequence of SEQ ID NO:3 and a VL region comprising the amino acid sequence of SEQ ID NO: 16. The
Reference Antibody is an IgG4 humanized monoclonal antibody that binds to PCSK9. See, e.g., GenBank: AJM94338.1 and AEX16238.1 for the Reference Antibody heavy and light chain sequences, respectively. For additional information about the Reference Antibody, see, e.g., US Pat. Nos: US8,080,243 and US10,472,424, U.S. patent application Ser. No. 14/232,559, published Jun. 12, 2014 as US20140161821 and Ridker et al., Am Heart J. 178:135-44 (2016), the contents of which are incorporated herein by reference in their entireties. (Para 0050)
The instant specification teaches that the term "paratope" refers to a set of amino acid residues in an antibody or an antigen-binding fragment thereof that contribute to a binding interaction with an epitope of a target protein. The binding interaction can be a hydrogen bond, a salt bridge, a van der Waal interaction, an ionic bond or a combination thereof. A binding interaction may be direct, or indirect, e.g., via a coordinated intermediate molecule, such as an ion or water. The residues of a paratope, in some embodiments, comprise only residues that are part of a defined CDR. In other embodiments, the residues of a paratope further comprise one or more residues that are not part of a defined CDR.
The instant specification does not define the structural features of the paratope-epitope binding. Figures 2-3 indicate the paratope residues in the CDRs and Figure 4 shows paratope residues in the VH and VL of the Reference Antibody. The instant disclosure teaches that In some embodiments, the paratope comprises positions 31, 32, 33, 50, 99, 100, 101, 102 and 103 of the VH (any one of SEQ ID NO:3-14), and positions 29, 30, 31, 32, 49, 50, 53, 54, 55, 56, 91, 92 and 96 of the VL (any one of SEQ ID NOs:16-24). In some embodiments, the paratope comprises S31, Y32, Y33, E50, E99, R100, P101, L102 and Y103 of the VH (SEQ ID NO:3), and 129, S30, S31, A32, Y49, S50, Y53, R54, Y55, T56, R91, Y92 and R96 of the VL (SEQ ID NO: 16). (Para 0068) Table 5 (page 59) of the instant disclosure lists amino acid residues with allowable and non-allowable substitutions, however with 118 residues in the VH and 17 residues listed with 1-7 allowable possible substitutions and 107 residues in the VL with 12 residues listed with 1-5 allowable possible substitutions results in millions of possible sequences to be tested.
As detailed below the state of the art does not recognize that a person of ordinary skill in the art could envision a genus of antibodies defined by epitope or function.
The disclosed antibody clones are not representative of the claimed genus of antibodies. This is because when antibodies are raised to an antigen each monoclonal antibody raised comes from one unique cell with unique CDRs which are responsible for antibody binding, such that the structure of CDRs for one antibody cannot be considered representative of other antibodies with different CDRs that bind the same antigen or even substantially the same epitope. Notably, the epitope structure that one antibody binds on an antigen, do not inform the skilled artisan as to what other antibodies would bind the same or substantially the same structure.
The state of the art as it applies to the claimed invention:
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Biodrugs (2007), 21 (3): 145-156; page 146, section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al. Protein Science (2005), 14:246–248; page 246). 3D structural analyses of antibody-epitope binding highlights the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al. J Comput Chem (2005), 26(9):879-87; page 879).
Ladner (Biotechnology and Genetic Engineering Reviews (2007), 24(1): 1-30) teaches that competitive binding assays demonstrate that two antibodies bind to overlapping or non-overlapping epitopes but not the same epitope (page 3; paragraph 3), so for accurate epitope mapping techniques that can be used are large energy transfer between labeled antibody to an antigen, antigen fragment binding, competitive peptide and antigen binding to antibody, antigen or antibody mutation, antigen-antibody complex analysis by NMR, determination of the 3D crystal structure of the antigen-antibody complex or electron microscopy (pages 5-7).
Tiller (Annu Rev Biomed Eng, 2015, 17:191-216) teaches that the holy grail of antibody design is to accurately and reliably predict the sequences of antibodies that will bind with high affinity and specificity based solely on the sequence or composition of the antigen (section 3.1) and a computational approach has been developed named OptCDR to design CDRs of antibodies to recognize specific epitopes on a target antigen. The predicted CDR sequences must then be grafted into antibody scaffolds for evaluation (section 3.1). Despite these advances de novo design continues to be challenging because of several factors, including the difficulty in accurately predicting the conformation of CDR loops as well as the structures of antibody-antigen complexes for which there are no initial crystal structures (section 9). Further, Tiller teaches that another critical problem in antibody design is the need to simultaneously optimize multiple attributes of antibodies wherein methods aimed at designing CDRs of antibodies to ensure high affinity need to identify sequences that also maximize folding stability and solubility (section 9). Tiller further teaches that the rational approach of antibody design has not eliminated the need for immunization or screening but instead have focused such efforts to make them more productive (section 10).
Jespersen (Frontiers in Immunology 10: 298, 2019) teaches detailed information on the molecular interactions between an antibody and its cognate antigen target is currently only available from protein 3D structures of antibodies co-crystallized with their target antigen, and currently the protein databank (PDB) only contains ~600 of such antibody-antigen (Ab-Ag) structures (Introduction). Jesperson further teaches that sequence-based and structure-based methods are available for predicting B-cell epitopes for an antibody but many benchmark studies have, as expected, demonstrated that structure-based methods display superior performance compared to sequence-based methods. However, even the best current structure-based methods for B-cell epitope prediction have limited predictive power (introduction).
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 teaches 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.
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.
The “Reference Antibody” used in the instant disclosure is known in the art as seen in U.S. Patent 8,080,243 B2 (IDS entered 03/10/2025) which details the CDR, VH and VL sequence of an anti-PCSK9 antibody that is antagonistic and a method of treating hypercholesterolemia by administering the same. Ito (The Journal of Clinical Pharmacology, 57: 7-32, 2017; PTO-892) teaches that PCSK9 gene was discovered in the past decade and monoclonal antibodies alirocumab and evolocumab have been approved for the treatment of hypercholesterolemia while more are still in development (abstract). Ito further teaches that PCSK9 mAb are an effective treatment with a good safety profile (conclusion).
Accordingly, one skilled in the art would be unable to predict or envision a genus of antibodies that bind to PCSK9 with 95% sequence identity to the instant claimed SEQ ID NO: 3 and 16, that competes with the “Reference Antibody”; or that comprises the same paratope as one of the 11 VH/VL pairs recited in claim 3. Since the disclosure fails to describe a sufficient number of species to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
Claim Rejections - 35 USC § 102
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.
(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.
Claims 1, 21-23, 25-26, 29, 31, 39, 45-46, 48-50, and 52-54 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liang (WO 2010/029513 A2; PTO-892).
Regarding claims 1 and 22, Liang teaches an isolated antibody wherein the VH region comprises SEQ ID NO: 54 and the VL region comprises SEQ ID NO: 53 (claim 10-13), SEQ ID NO: 54 has 100% sequence identity to the instant claimed SEQ ID NO: 3 and SEQ ID NO: 53 has 100% sequence identity to the instant claimed SEQ ID NO: 16.
Regarding claim 21, Liang teaches wherein the antibody is humanized, human, or chimeric (claim 21).
Regarding claims 23 and 31, Liang teaches the present invention can encompass monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab', F(ab')2, Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, heteroconjugate antibodies (page 28, lines 31-33).
Regarding claims 25-26, Liang teaches wherein the antibody has an isotype that is selected from the group consisting of lgG2, IgG4 (claim 16).
Regarding claim 29, Liang teaches the light chain constant region can be a kappa or lambda constant region (page 64, lines 28-29).
Regarding claim 39, Liang teaches antibody clone PCSK9 affinity all under 1 uM (Table 4).
Regarding claim 45, Liang teaches the invention also encompasses fusion proteins comprising one or more fragments or regions from the antibodies or polypeptides of this invention (page 53, lines 13-14).
Regarding claims 46 and 48-49, Liang teaches the invention also provides isolated polynucleotides encoding the antibodies and peptides of the invention, and vectors and host cells comprising the polynucleotide (page 54, lines 26-27).
Regarding claim 50, Liang teaches a pharmaceutical composition comprising a therapeutically effective amount of the antibody of claim 2 (claim 18).
Regarding claim 52, Liang teaches an isolated anti-PCSK9 antibody which specifically binds to PCSK9 and which is a full antagonist of the PCSK9-mediated effect LDL receptor (LDLR) levels as measured in vitro using an LDLR down-regulation assay in Huh7 cells (claim 2).
Regarding claim 53-54, Liang teaches an antagonist of PCSK9 which comprises an isolated antibody, a peptide, or an aptamer which interacts with PCSK9 and, when administered to a subject, lowers the blood low density lipoprotein (LDL) cholesterol in said subject (claim 1).
Allowable Subject Matter
Claims 5 and 20 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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