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 .
Claim Status
Claims 2-4, 12, 19, 24-25, and 28-39 have been cancelled and claims 5-6 and 8 have been amended, as requested in the amendment filed on 02/10/2026. Following the amendment, claims 1, 5-11, 13-18, 20-23, and 26-27 are pending in the instant application.
Claims 5-6 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and claims 14-15 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species in the Response filed 08/19/2025, there being no allowable generic or linking claim.
Claims 1, 7-11, 13, 16-18, 20-23, and 26-27 are under examination in the instant office action.
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 1, 7-11, 13, 16-18, 20-23, and 26-27 have an effective filing date of December 10, 2019 corresponding to PRO 62/946,268.
Information Disclosure Statement
The information disclosure statement filed 02/10/2026 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein, listed below, has not been considered because no copy and/or no legible copy, of the references have been provided:
Foreign Reference Citation Nos: 16 and 41; and
Non-Patent Literature Citation Nos: 31, 197, 199, 338, 374, 379, 398, 419, 431, 433, 450, and 488.
Specification - Objection Withdrawn
Applicant has submitted a substitute specification wherein trade names and/or marks used in commerce are properly represented. As such, the objection to the specification is withdrawn.
Claim Objections - Withdrawn
Claim 8 was objected to for a minor informality. Claim 8 has been amended to clarify the recited genotype limitation. As such, the objection to claim 8 is withdrawn.
Double Patenting - Withdrawn
Claims 1, 7-11, 13, 16-18, 20-23, and 26-27 were provisionally rejected over: (i) claims 50-51, 54-57, 59-62, and 68 of copending Application No. 14/316,587; and (ii) claims 2-6, 9-10, 12, 14, 16, 18, 20, 22-24, 28-29, and 35 of copending Application No. 17/011,433, each in view of US 2014/0356371 A1 (herein after referred to as "Swergold"; previously cited on PTO-892) and non-patent literature by Raal and Santos (Atherosclerosis, 2012, 223, 262-268; herein after referred to as "Raal"; previously cited on PTO-892).
Applicant has indicated that above-listed copending applications do not have a common assignee, applicant, or inventor with the instant application. Upon further review, it has been confirmed that the above-listed copending applications do not have a common assignee, applicant, or inventor with the instant application. As such, the provisional rejections of claims 1, 7-11, 13, 16-18, 20-23, and 26-27 under nonstatutory double patenting over copending Application No. 14/316,587 and copending Application No. 17/011,433 are withdrawn.
Claim Interpretation
It is noted that claim 1 has been amended with regard to the hPCSK9 inhibitor that is an antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof “comprises a heavy chain complementarity determining region (HCDR) 1 having an amino acid sequence of SEQ ID NO: 2, a HCDR2 having an amino acid sequence of SEQ ID NO: 3, a HCDR3 having an amino acid sequence of SEQ ID NO: 4, a light chain complementarity determining region (LCDR) 1 having an amino acid sequence of SEQ ID NO: 7, a LCDR2 having an amino acid sequence of SEQ ID NO: 8, and a LCDR3 having an amino acid sequence of SEQ ID NO: 10”. It is noted that with regard to the sequence language, the recitation of “an amino acid sequence” is being interpreted as “open” sequence language such that the recitation of, for example, “a heavy chain complementarity determining region (HCDR) 1 having an amino acid sequence of SEQ ID NO: 2” is being interpreted such that any amino acid sequence comprising at least two consecutive amino acids of SEQ ID NO: 2 is sufficient to meet the limitation. This interpretation applies to all of the recited CDRs in amended claim 1.
Claim Rejections - 35 USC § 112 - Maintained
Claims 1, 7-11, 13, 16-18, 20-23, and 26-27 stand as 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.
With regard to claim 1, it is acknowledged that the claim has been amended to recite that the hPCSK9 inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to hPCSK9 and “comprises a heavy chain complementarity determining region (HCDR) 1 having an amino acid sequence of SEQ ID NO: 2, a HCDR2 having an amino acid sequence of SEQ ID NO: 3, a HCDR3 having an amino acid sequence of SEQ ID NO: 4, a light chain complementarity determining region (LCDR) 1 having an amino acid sequence of SEQ ID NO: 7, a LCDR2 having an amino acid sequence of SEQ ID NO: 8, and a LCDR3 having an amino acid sequence of SEQ ID NO: 10”. However, it is noted that claim 1 still generically recites “the hPCSK9 inhibitor is an antibody or antigen-binding fragment thereof”. As noted in the previous Office Action (10/01/2025), the specification generically defines “antibody” as an immunoglobulin molecule comprising four polypeptide chains (two heavy and two light chains) and multimers thereof, and as such the definition provided by the specification indicates that an antibody may be monoclonal or polyclonal (further supported by embodiments that specify the use/generation of monoclonal antibodies) (Paragraph 0061) and therefore the claim is considered to have multiple structural interpretations with regard to CDR/antibody organization. An antibody may comprise all six recited CDRs and still be a monoclonal antibody (comprising a single antibody molecule) or a polyclonal antibody (comprising multiple antibody molecules that together form a functional antibody). As such, claim 1 is still considered to be indefinite due to multiple structural interpretations. Furthermore, the transitional phrase “having an amino acid sequence of” renders the claim indefinite with regard to the CDRs as it is unclear if this transitional phrase is intended to be “closed” such that the full-length sequences listed are required or if the phrase is intended to be “open” such that fragments of the sequences listed are also included; under BRI the claim is being interpreted such that “set forth in” is considered to be “open” claim language. As such, claim 1, specifically with regard to the recited CDRs, is considered to be indefinite. Claims 7-11, 13, 16-18, 20-23, and 26-27 are included in this rejection as they depend from and/or incorporate claim 1.
Claims 1, 7-11, 13, 16-18, 20-23, and 26-27 stand as rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a hPCSK9 inhibitor that is a monoclonal antibody comprising HCDRs 1-3 and LCDRs 1-3 corresponding to SEQ ID NOs: 2/3/4 and 7/8/10, respectively, does not reasonably provide enablement for any antibody (e.g., polyclonal) that comprises three HCDRs and three LCDRs which may be truncated. 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.
The Breadth of the Claims - As Amended
Claim 1 currently reads “wherein the hPCSK9 inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to hPCSK9 and comprises a heavy chain complementarity determining region (HCDR) 1 having an amino acid sequence of SEQ ID NO: 2, a HCDR2 having an amino acid sequence of SEQ ID NO: 3, a HCDR3 having an amino acid sequence of SEQ ID NO: 4, a light chain complementarity determining region (LCDR) 1 having an amino acid sequence of SEQ ID NO: 7, a LCDR2 having an amino acid sequence of SEQ ID NO: 8, and a LCDR3 having an amino acid sequence of SEQ ID NO: 10”. It is specifically noted that the claim recites “an amino acid sequence”, which is considered to be “open” sequence language wherein any amino acid sequence comprising at least two consecutive amino acid residues of the recited SEQ ID NOs meet the limitation; thus, instant claim 1 as amended can still include truncated CDRs under broadest reasonable interpretation. Additionally, at [0061] the specification generically defines “antibody” as an immunoglobulin molecule comprising four polypeptide chains (two heavy and two light chains) and multimers thereof; as such the definition provided by the specification indicates that an antibody may be monoclonal or polyclonal (further supported by embodiments that specify the use/generation of monoclonal antibodies); therefore the claim is considered to have multiple structural interpretations with regard to CDR/antibody organization. As such, claim 1 is extremely broad and is drawn to a genus of antibodies having multiple structural interpretations, wherein not all structural interpretations are enabled by the instant disclosure.
The State of the Prior Art/Level of Predictability in the Art
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”; previously cited on PTO-892). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30; emphasis added).
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93; previously cited non PTO-892) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a murine or humanized antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antibody fragments and mutated antibodies of the instant claims as broadly as claimed.
In the case of antibodies, it is especially important to disclose which residues are permissive to mutation. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982; previously cited on PTO-892). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect antibody structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibodies comprising truncated parental CDRs, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
At paragraph 0096 of the specification, one species of antibody comprising the recited CDRs has been adequately described, specifically, the antibody with the secondary identifier mAb316P, REGN727, or alirocumab. It is further noted that said antibody comprises HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 amino acid sequences of SEQ ID NOs: 2/3/4/7/8/10, respectively, and the antibody is a monoclonal antibody. This antibody has been adequately described by the recitation of six CDRs, wherein the organization/positions of the CDRs is specified. No other combinations of the recited CDRs of claim 1 (i.e., the CDRs in any other order), antibodies comprising truncated versions of said CDRs, nor polyclonal antibodies are provided.
In view of the of the breadth of the claims, the level of predictability in the art to which the invention pertains, as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibodies and antigen-binding fragments thereof comprising CDRs which can be truncated and/or polyclonal antibodies with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
Claims 1, 7-11, 13, 16-18, 20-23, and 26-27 stands as 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 claims are drawn to a genus of antibodies that specifically bind hPCSK9, which comprise three heavy chain CDRs (HCDRs 1-3) “having an amino sequence of” SEQ ID NOs: 2, 3, and 4, respectively, and three light chain CDRs (LCDRs 1-3) “having an amino sequence of” SEQ ID NOs: 7, 8, and 10, respectively (see claim 1). It is unclear as to if the transitional phrase “having an amino acid sequence of” is intended to be “closed” or “open” language, and as such under BRI is being interpreted as “open”; as such truncations of the recited CDR sequences fall within the scope of the claim. At paragraph 0096 of the specification, one species of antibody comprising the recited CDRs has been adequately described, specifically, the antibody with the secondary identifier mAb316P, REGN727, or alirocumab; said antibody comprises HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 amino acid sequences of SEQ ID NOs: 2/3/4/7/8/10, respectively. This antibody has been adequately described by the recitation of six CDRs, wherein the organization/positions of the CDRs is specified. However, even though Applicant has a species of antibody that specifically binds hPCSK9, Applicant is claiming a large and structurally diverse genus of hPCSK9-specific antibodies, each of which comprise one of numerous possible combinations of the recited CDRs. Absent empirical determination, 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 combinations of the recited CDRs yield antibodies that are capable of binding hPCSK9. Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and 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.
PNG
media_image1.png
18
19
media_image1.png
Greyscale
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. As previously indicated, Applicant has disclosed one species within the genus claimed. However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of said single adequately described species is not sufficiently representative of the entire genus.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR amino acid sequences (or combinations/truncations thereof) that confer upon an antibody the ability to bind hPCSK9. It is well-known in the art that single domain binding proteins generally comprise six CDRs. The amino acid sequences of the CDRs are hypervariable, and the amino acid residues contained within the three CDRs determine the antigen specificity of a particular antibody. Absent a description of the at least minimal structural features correlating with a functional ability to bind hPCSK9 which are shared by members of a genus of antibodies commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which combinations/order of CDR amino acid sequences (or truncations thereof) may be combined such that the resultant antibody comprises six CDRs that confer the ability to bind hPCSK9.
Although screening techniques can be used to isolate antibodies that possess the ability to bind hPCSK9, 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 difficulty associated with predicting CDR combinations (including truncations thereof) that yield antibodies capable of binding hPCSK9 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 instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1, 20-23, and 26-27 stand as rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0356371 A1 (herein after referred to as "Swergold"; previously cited on PTO-892).
Claims 7-11, 13, and 16-18 stand as rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0356371 A1 (herein after referred to as "Swergold"; previously cited on PTO-892) as applied to claims 1, 7, 18, 20-23, and 26-27 above, and further in view of non-patent literature by Raal and Santos (Atherosclerosis, 2012, 223, 262-268; herein after referred to as "Raal"; previously cited on PTO-892).
Double Patenting - Maintained
Claims 1, 7-11, 13, 16-18, 20-23, and 26-27 stands as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. in view of US 2014/0356371 A1 (herein after referred to as "Swergold") and non-patent literature by Raal and Santos (Atherosclerosis, 2012, 223, 262-268; herein after referred to as "Raal").
Application No.
Brief Description of the Invention
Pertinent Claims
18790032
Method for Treating a Disease Related to PCSK9 Activity Comprising Administering hPCSK9 Antibody
30-45
18786917
Method for Treating Hypercholesterolemia Comprising Administering hPCSK9 Antibody
93-100, 105-107
18407331
Method of Eliminating Patient's Need for Lipoprotein Apheresis Comprising Administering PCSK9 Antibody
1, 5-6, 8-9, 12, 15-17, 21, 23-25
18308769
Method for Preparing Composition Comprising PCSK9 Antibodies
31, 35-36
18301638
Method for Reducing LDL-C Comprising Administering PCSK9 Antibody
79-81, 85, 88-89, 91
Claims 1, 7-11, 13, 16-18, 20-23, and 26-27 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed U.S. Patent Nos. in view of US 2014/0356371 A1 (herein after referred to as "Swergold") and non-patent literature by Raal and Santos (Atherosclerosis, 2012, 223, 262-268; herein after referred to as "Raal").
It is noted that the table below has been amended to remove the duplicate recitation of U.S. Patent No. 11,904,017.
Patent No.
Brief Description of the Invention
Pertinent Claims
8795669
Liquid Pharmaceutical Composition Comprising PCSK9 Antibody
1-2, 12-16
9193801
Pre-Filled Syringe Composition Comprising PCSK9 Antibody Formulation
1, 8, 18-22
9550837
Method for Treating a Subject Comprising Administering hPCSK9 Antibody
1, 4-5, 8, 10
9561155
Method for Treating PCSK9 Activity-Related Disease/Condition Comprising Administering PCSK9 Antibody
1-20, 23-25
9682013
Unit Dosage Form of Pharmaceutical Composition Comprising PCSK9 Antibody
1-10, 13-15
9724411
Method for Treating Hypercholesterolemia Comprising Administering PCSK9 Antibody
1-4, 7-8, 12, 14-15, 17-20, 23-24, 28, 30-31
10023654
Anti-hPCSK9 Antibody
1, 4, 7, 10, 13, 16
10111953
Method for Reducing Serum LDL-C Comprising Administering PCSK9 Antibody
1, 3-4, 7-8
10428157
Method for Reducing LDL-C Comprising Administering PCSK9 Antibody
1-3, 5-6, 8, 12-13
10472425
Pharmaceutical Formulation Comprising PCSK9 Antibody
1-8
10494442
Method of Inhibiting Atherosclerotic Plaque Formation Comprising Administering PCSK9 Antibody
1, 3, 6, 8, 12, 18-20
10544232
Method for Treating Hypercholesterolemia Comprising Administering PCSK9 Antibody
1-3, 6-8, 12
10752701
Pre-Filled Syringe Composition Comprising PCSK9 Antibody Formulation
1, 8, 15
10772956
Method of Eliminating Patient's Need for Lipoprotein Apheresis Comprising Administering PCSK9 Antibody
1, 5-9, 14-17
10941210
Nucleic Acid Molecule Comprising Nucleotides Encoding a PCSK9 Antibody and the Antibody Thereof
1-2, 5-6, 8
10995150
Method of Inhibiting Progression of Atherosclerosis Comprising Administering PCSK9 Antibody
1, 9, 11, 15-16, 18-19
11116839
Method of Reducing Lipoprotein(a) Comprising Administering PCSK9 Antibody
1-2, 6, 8-9, 13-18, 21-22
11246925
Method for Treating Primary Hyperlipidemia Comprising Administering hPCSK9 Antibody
1-11, 13
11306155
Method for Reducing LDL-C Comprising Administering PCSK9 Antibody
1-2, 5, 7-8, 11, 13-14
11306155
Method for Reducing LDL-C Comprising Administering PCSK9 Antibody
1-2, 5, 7-8, 11, 13-14
11673967
Pre-Filled Delivery Pen Device Comprising PCSK9 Antibody Formulation
1-3
11904017
Method of Eliminating Patient's Need for Lipoprotein Apheresis Comprising Administering PCSK9 Antibody
1-2, 8-9, 11, 13, 15-20
12083176
Pharmaceutical Composition Comprising hPCSK9 Antibody
1-10
12281173
Method of Treating Patient Suffering from Familial Hypercholesterolemia Comprising Administering PCSK9 Antibody
1-11
Response to Arguments
Applicant's arguments filed 02/10/2026 (herein after referred to as "Remarks") have been fully considered but they are not persuasive.
With regard to the above-listed maintained claim rejections under 35 U.S.C. 103, Applicant argues the following on Pages 8-12 of Remarks:
Swergold is directed broadly to methods for reducing lipoproteins in patients with hypercholesterolemia and related conditions. While Swergold includes hoFH among a list of hypercholesterolemia conditions, it does not provide any experimental data, exemplification, or clinical guidance specific to hoFH patients. HoFH is a uniquely severe and biologically distinct condition characterized by little or no functional LDL receptor activity. This patient population was well recognized at the time of filing as particularly difficult to treat and as responding poorly to standard lipid-lowering therapies, including statins, and as typically requiring aggressive interventions such as LDL apheresis; Swergold does not address these biological limitations, nor does it explain why or how PCSK9 inhibition would be expected to be effective in patients with severely impaired or absent LDL receptor function. Accordingly, Swergold's generalized discussion of hypercholesterolemia treatment does not amount to a teaching or suggestion of the claimed method for treating hoFH patients.
Swergold does not establish that administering a PCSK9 antibody would successfully reduce LDL-C in hoFH patients, nor does it provide any data demonstrating efficacy in this patient population. At most, Swergold proposes a hypothesis that PCSK9 inhibition may be broadly useful in lipid disorders. Such speculative disclosure does not rise to the level of a reasonable expectation of success, particularly in view of the known unpredictability of antibody-based therapies in genetically distinct and refractory patient populations such as hoFH.
Routine optimization regarding dosing and administration schedules does not apply; a parameter must first be recognized in the prior art as a result-effective variable before optimization of that parameter can be considered routine and this condition is not satisfied for hoFH patients: The result itself was not established because (i) Swergold does not establish that PCSK9 antibody treatment is effective in hoFH patients at any dose or schedule and (ii) the system is not predictable because the response of hoFH patients to lipid-lowering therapies was known to be highly variable and unpredictable due to underlying genetic defects in LDL receptor pathways. Where the underlying therapeutic effect is uncertain, identifying a dose or dosing schedule cannot be dismissed as routine optimization. Instead, determining whether any dose or regimen would be effective would require extensive clinical investigation amounting to a research program, not routine experimentation.
Although Swergold discloses an anti-PCSK9 antibody having sequences corresponding to those recited in the claims, disclosure of a molecule does not render all therapeutic uses of that molecule obvious; the present claims are directed to a specific therapeutic application of treating hoFH patients, including statin-intolerant or statin-refractory patients, under conditions where success was not predictable, and the fact that the antibody itself was known does not supply the missing motivation or expectation of success required to render the claimed method obvious.
Swergold fails to teach or suggest the claimed method of treating hoFH patients with a reasonable expectation of success. Raal does not cure these deficiencies. While Raal describes diagnostic criteria and clinical characteristics of hoFH patients, it does not teach or suggest that treatment with a PCSK9 antibody, as disclosed in Swergold, would be effective in such patients, nor does it provide any basis for a reasonable expectation of success. Accordingly, claim 1 remains non-obvious over Swergold, whether considered alone or in combination with Raal.
The rejection(s) rely on impermissible hindsight in its interpretation of Swergold alone and in combination with Raal. The analysis reconstructs the claimed invention by selectively extracting generalized disclosures from Swergold and, where applicable, supplementing them with background information from Raal, using Applicants' disclosure as the unifying principle. This approach relies on hindsight knowledge of Applicants' results rather than on teachings that would have been available to a person of ordinary skill in the art at the time of filing.
With regard to the above arguments against Swergold, it is specifically noted that the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970). Thus, while Swergold may not provide specific examples and/or data pertaining to the treatment of patients having hoFH, Swergold does explicitly teaches that “a patient may be selected for treatment with the
methods of the present invention if the patient is diagnosed with or identified as being at risk of developing a hypercholesterolemia condition such as, e.g., heterozygous Familial Hypercholesterolemia (heFH), homozygous Familial Hypercholesterolemia (hoFH), Autosomal Dominant Hypercholesterolemia (ADH, e.g., ADH associated with one or more gain-of-function mutations in the PCSK9 gene), as well as incidences of hypercholesterolemia that are distinct from Familial Hypercholesterolemia (nonFH)” (Paragraph 0039) wherein said treatment methods of the invention comprise administering a PCSK9 inhibitor, wherein said PCSK9 inhibitor may be an antibody. Swergold further teaches that methods of the invention may also be used for patients who are intolerant of, non-responsive to, or inadequately responsive to conventional statin therapy (Paragraph 0041). Thus, Swergold explicitly indicates that hoFH patients, including patients intolerant to, non-responsive to, or inadequately responsive to statins, are a patient population suitable for treatment comprising administering a PCSK9 inhibitor (e.g., and antibody). Regarding “treatment”, it is specifically noted that Swergold indicates that PCSK9 is a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family, wherein the use of PCSK9 inhibitors (anti-PCSK9 antibodies) reduces serum total cholesterol, LDL cholesterol and serum triglycerides (Paragraph 0004). Thus, absent evidence to the contrary, Swergold enables the treatment of hoFH patients who are intolerant of and/or non-responsive (i.e., refractory) treatment with statins wherein said treatment comprises administering a PCSK9 inhibitor (e.g., an antibody) which functions to lower serum total cholesterol, LDL cholesterol and serum triglycerides. PCSK9 inhibitors which may be administered in accordance with the methods of the present invention include, e.g., anti-PCSK9 antibodies or antigen-binding fragments thereof (Paragraph 0008); the antibody or antigen-binding fragment thereof comprises the six CDRs (HCDRl, HCDR2, HCDR3, LCDRl, LCDR2 and LCDR3) from the heavy and light chain variable region amino acid sequence pairs (HCVR/LCVR) selected from a group that includes SEQ ID NOs: 90 and 92 (Paragraph 0071) wherein it is specifically noted that Swergold SEQ ID NOs: 90 and 92 comprise 100% matches for HCDRs 1-3 and LCDRs 1-3 of instant SEQ ID NOs: 2/3/4 and 7/8/10, respectively, and are also 100% matches to instant SEQ ID NOs: 1 and 6, respectively. Treatment regimens according to the method (including doses and dosing schedules) are also disclosed by Swergold (see, for example, Paragraphs 0085-0090). With regard to the argument that routine optimization does not apply to the doses/dosing schedule, it is specifically noted that Swergold indicates that: (i) the amount of PCSK9 inhibitor (e.g., anti-PCSK9 antibody) administered to a subject according to the methods of the invention is, generally, a therapeutically effective amount. wherein the phrase "therapeutically effective amount" means a dose of PCSK9 inhibitor that results in a detectable reduction in one or more parameters selected from the group consisting of remnant cholesterol (RLP-C), VLDL-C, VLDL1 -C, VLDL2-C, VLDL1+ 2 -C, VLDL3-C, IDL-C, LDL1 -C, LDL2-C, LDL3-C, LDL4 -C, LDL3+4 -C, further wherein animal models can be used to establish whether a particular amount of a candidate PCSK9 inhibitor is a therapeutically effective amount (Paragraph 0081); and (ii) the frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination (Paragraph 0089). Thus, Swergold suggests that the doses and dosing schedules of PCSK9 inhibitors can be adjusted (i.e., optimized) in order to achieve desired effects. Thus, it is maintained that the teachings of Swergold render obvious the method of instant claim 1, wherein based on the teachings of Swergold it would reasonably be expected that the administration of a PCSK9 inhibitor (e.g., the instantly claimed antibody) to the instantly claimed patient population would result in a reduction of serum total cholesterol, LDL cholesterol, and serum triglycerides.
It is noted no specific arguments against Raal have been provided, but rather the argument regarding the claim rejection under 35 U.S.C. 103 in view of Swergold and Raal cites the alleged deficiencies in Swergold, which have been addressed above.
With regard to the argument of impermissible hindsight, “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). The entire disclosure of Swergold, and subsequently Raal, were available and within the level of ordinary skill in the art; Swergold discloses all of the limitations of instant claim 1, and one of ordinary skill in the art could have reasonably used/combined the individual teachings of Swergold, based on the suggestions of Swergold, to arrive at instant claim 1. Thus, the claim rejections listed above under 35 U.S.C. 103 in view of Swergold and Raal are deemed proper.
Thus, in view of the above, the above-listed claim rejections under 35 U.S.C. 103 over Swergold and the claim rejections under 35 U.S.C. 103 over Swergold in further view of Raal are maintained.
With regard to the above-listed maintained claim rejections under nonstatutuory double patenting, Applicant argues the following on Pages 13-16 of Remarks:
The double patenting rejections of record do not meet the requirements of a non-statutory double patenting rejection as established by the MPEP. Each claim that stands rejected is not individually compared to a claim in the reference patent, and all pertinent claims of cited patents are relied on together in the statement of rejection. Clearly, the Examiner has not performed a claim-by-claim analysis as is required. Thus, the rejections are not proper since the Examiner has not set forth a prima facie argument explaining why the claim are obvious.
With regard to the above, it is noted that an exemplary claim-by-claim analysis of a previously cited reference application was provided, and the prima facie case for obviousness was established. It was acknowledged that the additionally listed claim rejections were similarly rejected under nonstatutory double patenting over the cited reference applications and reference patents in view of Swergols and/or Raal. It is noted that the provided pertinent claims are the only claims of the reference applications/patents that read directly on the instant claim set. The nexus providing the basis of rejection shared among all of the cited reference applications and reference patents was explicitly provided; all of the cited reference applications and reference patents are specifically drawn to anti-PCSK9 antibodies, compositions, and/or therapeutic methods relating to conditions associated with high levels of lipoproteins. Furthermore, the obviousness analysis regarding said nexus, based on the teachings of the prior art established in the 103 sections (which renders all of instant claims obvious), was provided. The reference applications and/or reference patents could reasonably be modified such that anti-PCSK9 antibodies matching the instantly claimed sequences, as taught by the reference patents and/or Swergold, could be utilized in a method for treating hoFH in a patient, wherein said patient is intolerant to statins, comprising administering a hPCSK9 inhibitor (i.e., antibody) to the patient at a frequency of, for example, once every two weeks, as suggested by Swergold, wherein such a method would be expected to reduce lipoprotein levels in the patient thereby treating hoFH with a reasonable expectation of success. Swergold teaches all of the limitations of instant claim 1, and Raal discloses additional limitations of the dependent claims, and thus any reference application or reference patent drawn to anti-PCSK9 antibodies, compositions, and/or therapeutic methods relating to conditions associated with high levels of lipoproteins could reasonably be modified to arrive at the instantly claimed methods based on the teachings of Swergold and Raal.
Thus, in view of the above, the above-listed claim rejections under nonstatutuory double patenting over the reference applications and/or reference patents, Swergold, and Raal are maintained.
It is further noted that with regard to the above-listed provisional claim rejections under nonstatutory double patenting, Applicant has provided no arguments and has requested the rejections be held in abeyance until allowable subject matter is identified. As such, the above-listed provisional claim rejections under nonstatutory double patenting are maintained.
Conclusion
Claims 1, 5-11, 13-18, 20-23, and 26-27 are pending. Claims 5-6 are withdrawn. Claims 1, 7-11, 13, 16-18, 20-23, and 26-27 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
Prosecution Insights