DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed on 11/12/25 has been entered; no amendments are indicated. Claims 21-40 are pending.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
The elections of (1) an antibody with the VH/VL of SEQ ID NO: 25/26 as the species of CD14 antagonist antibody, and (2) aspirin as the species of ancillary agent, in the reply filed on 11/12/25 are acknowledged. Claims 35 and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 21-34 and 37-40 are under consideration, as they read upon the elected species.
Specification
The disclosure is objected to because of the following informalities:
---The title of the invention is not descriptive because (1) in part it is directed generally to any method for treatment of myocardial infarction but the pending claims are limited to such methods effected by administration of an CD14 antagonist antibody; and (2) in part it is directed to agents, which are products, but the pending claims are limited to methods of use. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “Therapeutic Methods for the Treatment of Myocardial Infarction with a CD14 Antagonist Antibody”
Appropriate correction is required.
Claim Objections
Claims 31 and 37 are objected to because of the following informalities:
In claim 31, line 3, “sequence” should be “sequence:” Compare with line 8.
In claim 37, line 2, “a P2Y12 inhibitors” should be “a P2Y12 inhibitor”.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a), written description
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 21-27, 30, 32-34 and 37-40 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.
Per MPEP 2163, 35 U.S.C. 112(a) requires, “separate and distinct from the enablement requirement”, that the “specification shall contain a written description of the invention…” (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The instant claims are directed to a method intended for the treatment of myocardial infarction (MI) in a subject. The method is intended to achieve this goal via a single step of administration, to the subject, of a CD14 antagonist antibody. The specification teaches that the “invention arises in part from the surprising determination that targeting Cluster of Differentiation 14 (CD14), such as by administration of an anti-CD14 antagonist antibody, can reduce or ameliorate the cardiac damage resulting from MI” (¶ 8, published application). The specification then elaborates that “it has been demonstrated for the first time herein that administration of a CD14 antagonist antibody following STEMI, the most severe form of MI, improved systolic function, contractile properties and haemodynamic function of the heart (e.g. increased stroke volume, cardiac output, ejection fraction, stroke work and dV/dt max, and reduced dV/dt min) and decreased infarct size and reduced fibrosis compared to when the antibody was not administered” (¶ 8) and that “[t]his clear improvement in multiple MI parameters, representing a significant improvement in cardiac efficiency and function, is surprising for any one agent and particularly for an anti-CD14 agent given previous findings that suggested that targeting CD14 would have no effect on preventing or ameliorating the deleterious consequences of MI infarct size or contractile properties…” (¶ 8).
While the claims are directed to a method of a product (i.e., antibody) rather than claiming a product per se, practicing said method requires a written description of the product to be used in the method. The product of the claims, the CD14 antagonist antibody, is defined structurally as being an antibody, and functionally as being an “CD14 antagonist”. The specification teaches that the “term “antagonist antibody” is used in the broadest sense, and includes an antibody that inhibits or decreases the biological activity of an antigen to which the antibody binds (e.g., CD14)” (¶ 44). While this definition includes an antibody that binds to CD14, it is not limiting and broadly encompasses antibodies that bind to other targets to indirectly result in antagonism of CD14.
The prior art recognizes that antibodies bind to epitopes of 5-7 amino acids (Benjamini et al, 1991. Immunology: A Short Course, 2nd edition, page 40 only). The CD14 protein is 375 amino acids in length (see page 1 of Anas et al, 2010. Critical Care. 14:209; 8 pages as printed). Thus, even considering only continuous epitopes, CD14 comprises a multitude of different regions of five amino acids that can serve as epitopes; i.e., residues 1-5, 2-6, 3-7, up to residues 371-375. While the general structure of an antibody was well-known in the prior art, it is the structure of the complementarity-determining regions (CDRs) that determines the specificity of a particular antibody, and said CDR structure is not predictable based on the epitope to which it binds. Thus, even knowing the structure (CDRs) of one antibody does not allow the skilled artisan to predict the structure of other antibodies that bind to the same epitope or to the other epitopes in the same protein. The relevant art, Ferrara et al (2015. mAbs. 7(1): 32-41) teaches that there is substantial variation in the structure of antibodies that bind to a single protein, on the order of hundreds of different sequences; specifically, see page 36: "The number of different HCDR3s selected against the test antigens ranges from 74 to 460 (Table 3), with the actual number of different antibodies likely to be significantly higher when different VL chains and additional VH mutations are taken into account” (pg 36). Thus, there are at least hundreds of different antibody structures that bind to the CD14 protein, some of which will function as antagonists of the protein. Thus the claims are genus claims, because they are directed to a method of use of a genus of CD14 antagonist antibodies.
A product defined by function is not in and of itself sufficient to describe the product because it is only an indication of what the product does, rather than what it is; i.e., the specific structure of the product. It is only a definition of a useful result rather than a definition of what achieves that result. Per MPEP 2124, "describing a composition by its function alone typically will not suffice to sufficiently describe the composition". Furthermore, in the instant case the specification does not establish a correlation between structure and function; e.g., the structure of one CD14 antagonist antibody does not provide predictability regarding the range of other antibody structures having the same functionality. Furthermore, the decision of the Federal Circuit in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Circ. 2017) held that a claim directed to an antibody requires written description of the antibody itself rather than being satisfied solely by a written description of the antigen to which it binds (the so-called "newly characterized antigen" test). Thus, a description of the target protein (e.g. CD14) is not in and of itself sufficient to provide a description of the genus of antibodies antagonizing CD14.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[A] sufficient description of a genus … requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
In support of the claimed genus of CD14 antagonist antibody, the specification provides examples of four monoclonal antibodies that bind CD14, antagonize the protein function and are defined by their amino acid sequences. These include the antibodies 3C10, 28C5, IC14 and 18E12, the sequences of which are recited in the alternative in each claims 28, 29 and 31. The elected species under consideration, IC14, is described by the specification as “a chimeric (murine/human) monoclonal antibody that specifically binds to human CD14. IC14 was derived from the murine 28C5 noted above and comprises an IgG4 heavy chain” (¶ 99, published application). The disclosure of the amino acid sequences of these antibodies is sufficient to provide a written description for antibodies comprising these sequences.
The specification also provides references to several other CD14 antagonist antibodies known in the prior art (¶ 82, published application). However, the specification does not describe the amino acid sequences of these antibodies, or whether the amino acid sequences of these antibodies are disclosed in the art. The identification of a monoclonal antibody solely by name (e.g., a clone number) and functionality is not sufficient in and of itself to provide a written description of said antibody for the skilled artisan to be able to “possess” the antibody for use in the claimed method of treatment. In order for an antibody to be sufficiently described by the prior art, it must be obtainable by the practitioner, either by disclosure of the amino acid sequences and/or another means, e.g., availability as deposit.
A description of just four monoclonal antibodies by amino acid sequence, two of which have related sequences (IC14 and 28C5) is not representative of the genus of CD14 antagonist antibodies to be used in the claimed methods, which potentially encompasses hundreds or more species. Per MPEP 2163, "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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
Therefore, only a method for treating myocardial infarction (MI) in a subject comprising administering an effective amount of a CD14 antagonist antibody to the subject, wherein the CD14 antibody antagonist is selected from the group recited in claim 28, 29 or 31, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Prior Art Rejection(s)
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 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were effectively filed absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned at the time a later invention was effectively filed in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 21-40 are rejected under 35 U.S.C. 103(a) as being unpatentable over U.S. Patent Application Publication 2022/0249610, published 8/11/2022, filed 7/24/20, and claiming priority to 7/25/19, and further in view of Nolan, 2011. Clinical Medicine. 11(6): 605-608. The earliest date to which the instant application claims priority is 9/10/20.
Claim 21 encompasses a method for treating myocardial infarction (MI) in a subject comprising administering an effective amount of a CD14 antagonist antibody to the subject. The term “for treating myocardial infarction (MI) in a subject” is interpreted broadly as treating any of the effects of MI.
‘610 teaches “use of a CD14 antagonist antibody for the preparation of a medicament for treating acute neuroinflammatory injury (e.g. stroke, such as ischemic stroke or hemorrhagic stroke, hypoxic-ischemic brain injury, traumatic brain injury, subarachnoid hemorrhage or intracerebral hemorrhage) in a human subject” (¶ 19). ‘610 further teaches that “[h]ypoxic-ischemic brain injury can be the result of various diseases, insults or injuries, including, for example, cardiac arrest”. While ‘610 further teaches that the CD14 antagonist antibody is administered for treatment (¶ 7). While ‘610 teaches a method for treating hypoxic-ischemic brain injury resulting from cardiac arrest comprising administering an effective amount of a CD14 antagonist antibody, ‘610 does not teach such a method wherein the cardiac arrest is caused by myocardial infarction (MI).
Nolan teaches that cardiac arrest can be caused by MI, and can lead to “post- cardiac brain injury” due to “the prolonged period systemic ischaemia” (page 605).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the method for treating hypoxic-ischemic brain injury resulting from cardiac arrest comprising administering an effective amount of a CD14 antagonist antibody taught by ‘610 and modify the method to apply it to the subset of such cardiac arrest patients wherein the cardiac arrest is caused by MI as taught by Nolan. The person of ordinary skill in the art would have been motivated to make such a change in order to treat the brain injury in the patient with cardiac arrest caused by MI, and would have had a reasonable expectation of success in treating such patients because, in the absence of evidence to the contrary, would expect the method of ‘610 to work equally well with any type of patient having a hypoxic brain injury due to cardiac arrest. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Claims 22-25 further limit the antibody administration parameters of the claimed method. Claims 22 and 23 each encompass a method of claim 21 wherein the antibody is administered to the subject up to 48 hours post-MI. Claim 24 encompasses a method of claim 21 wherein the antibody is administered to the subject in 1, 2, 3 or more doses. Claim 25 encompasses a method of claim 21 wherein the antibody is administered systemically. ‘610 teaches each of these further parameters for administration, including that the antibody “can be administered to the subject up to 48 hours post-injury” (¶ 11); that the antibody can be administered in “one or more doses” (¶ 76); or that the antibody can be administered in systemically (¶ 77). As such, it would have further been obvious to employ any of these further antibody administration parameters taught by ‘610 when practicing the method of treatment obvious over the teachings of ‘610 in view of Nolan.
Claims 26 and 27 encompass a method of claim 21 wherein the MI is ST-segment elevation MI (STEMI) (claim 26) or non-ST-segment elevation MI (NSTEMI) (claim 27). Nolan further teaches that the cardiac arrest leading to brain injury can be caused by STEMI or NSTEMI (pages 605, 606). As such, it would have further been obvious to treat a subject having either of these types of MI when practicing the method of treatment obvious over the teachings of ‘610 in view of Nolan, because the skilled artisan would be motivated to treat a subject having a brain injury from either type of MI and would reasonably expect to treatment to work equally well with a brain injury caused by any type of MI.
Claims 28-31 further limit the administered antibody of the method of claim 21. Claims 28-29 and 31 each encompass a method of claim 21 wherein the CD14 antagonist antibody has sequences from the elected species of antibody IC14, defined either by the CDR sequences (claim 28), the VL/VH sequences (claim 29) or the LC/HC sequences (claim 31). Claim 30 encompasses a method of claim 21 wherein the antibody is humanized. ‘610 further teaches that the CD14 antagonist antibody has the sequences of the IC10 antibody (¶ 23), and that the antibody can be humanized (¶ 40). As such, it would have further been obvious to employ any of these CD14 antagonist antibodies taught by ‘610 when practicing the method of treatment obvious over the teachings of ‘610 in view of Nolan.
Claims 32-34 and 37 each encompasses a method of claim 21 wherein the antibody is administered to in combination with an ancillary agent (claim 32) that is a platelet inhibitor (claim 34) that is aspirin (claim 37) or that is administered simultaneously. ‘610 further teaches that the antibody can be administered in combination with ancillary agents such as aspirin (¶ 112) and can be administered simultaneously (¶ 113). As such, it would have further been obvious to employ any of these ancillary agents and administration parameters of such taught by ‘610 when practicing the method of treatment obvious over the teachings of ‘610 in view of Nolan.
Claim 38 encompasses a method of claim 21 wherein PCI is performed on the subject (claim 38). Nolan further teaches that PCI is “the preferred method for restoring coronary perfusion when cardiac arrest has been caused by ST-elevation myocardial infarction (STEMI)” (page 605). As such, it would have further been obvious to treat the subject having MI with PCI as taught by Nolan when practicing the method of treatment obvious over the teachings of ‘610 in view of Nolan.
Claim 39 encompasses a method of claim 38, wherein the CD14 antagonist antibody is administered within 72 hours of PCI. Nolan further teaches that “[i]f a first medical contact-to-balloon time of less than 90 minutes can be achieved, primary PCI is the preferred treatment” (page 605). As set forth above, ‘610 teaches that the CD14 antagonist antibody “can be administered to the subject up to 48 hours post-injury” (¶ 11). Thus, if primary PCI is administered in 90 minutes or less, and the antagonist antibody is administered with 48 hours post-injury, this means the antibody is administered within 72 hours of PCI. As such, it would have further been obvious to treat the subject having MI with PCI and administered the CD14 antagonist antibody within 48 hours of the injury as taught by Nolan when practicing the method of treatment obvious over the teachings of ‘610 in view of Nolan.
Claim 40 encompasses a method of claim 38 wherein the PCI is angioplasty. As set forth above, Nolan further teaches that “[i]f a first medical contact-to-balloon time of less than 90 minutes can be achieved, primary PCI is the preferred treatment” (page 605). The “balloon” here refers to an angioplasty balloon. As such, it would have further been obvious to treat the subject having MI with PCI that is a balloon (angioplasty) as taught by Nolan when practicing the method of treatment obvious over the teachings of ‘610 in view of Nolan.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674