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 .
Claims 1-56 are cancelled.
Claims 57 and 64 are currently amended.
Claim 71 is new.
Claims 57-71 are pending and under examination on the merits.
Priority
Applicant’s claim of priority to U.S. Patent Application No. 14/198,804, filed on March 6, 2014, which is a continuation of PCT Application No. PCT/US2012/053900, filed on September 6, 2012, which claims priority to U.S. Provisional Application No. 61/531,278, filed September 6, 2011, is acknowledged.
Withdrawn Objections and Rejections
The rejections of the claims under 35 USC §112(b) are withdrawn because the Examiner is further persuaded that the conversion to the claimed doses would be within the average skill of the artisan with sufficient clarity.
New-Claim Objections
Applicant is advised that should claim 67 be found allowable, claim 71 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Maintained-Claim Rejections - 35 USC § 112
35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 57-71 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The claims are drawn to a method of inhibiting disability or death from endogenous or pharmacologic tissue plasminogen activator (TPA) toxicity due to thrombosis in a lung in a patient in need thereof comprising administering to said patient an effective amount of an anti-SerpinF2 antibody or fragment thereof that reduces SerpinF2 activity or concentration, thereby inhibiting disability or death from TPA toxicity due to thrombosis in a lung.
Claim 57 is drawn to a method of inhibiting disability or death from endogenous or pharmacologic tissue plasminogen activator (TPA) mediated respiratory hemorrhage or edema in a patient in need thereof comprising administering to said patient an effective amount of an anti-SerpinF2 antibody or fragment thereof that reduces SerpinF2 activity or concentration, thereby inhibiting disability or death from TPA mediated neurologic hemorrhage or edema.
Claim 64 is drawn to a method of treating respiratory hemorrhage or edema from endogenous or pharmacologic tissue plasminogen activator (TPA) in a patient in need thereof comprising administering to said patient an effective amount of an anti-SerpinF2 antibody or fragment thereof that reduces SerpinF2 activity or concentration, thereby treating respiratory hemorrhage or edema from TPA toxicity.
The specification teaches that administration of SerpinF2 antibody increased the lysis of the thromboembolus (thrombus/clot). The specification teaches that treatment with SerpinF2 antibody markedly reduced mortality rates by comparison to TPA-treated mice (See paragraph 0068). The specification teaches that administration of SerpinF2 antibody reduced neuronal cell death compared to control or TPA treated mice. The specification teaches that administration of SerpinF2 antibody prevented brain hemorrhage and brain swelling compared to control and TPA treated mice. The specification teaches that treatment with SerpinF2 antibody prevented mice from disability as judged by their ability to maintain balance on a rotating cylinder (See paragraph 0068). The specification teaches that inhibition of SerpinF2 decreased the blood brain barrier breakdown and reduced brain cell death associated with apoptosis (See paragraph 0069).
The specification teaches that administration of SerpinF2 antibody with TPA markedly reduced neuronal damage compared to a standard and low dose of TPA alone. The specification teaches that administration of SerpinF2 with a standard dose of TPA reduced the hemorrhage caused by standard dose TPA alone (See paragraph 0070-0071). The specification teaches that mortality was 0% after thromboembolic stroke in mice treated with TPA and SerpinF2 antibody compared to 78% mortality in mice treated with TPA alone. The specification teaches that the combination of TPA and SerpinF2-inhibitor significantly reduced hemispheric swelling by comparison to TPA alone (See paragraph 0072).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
The claims are drawn to method of inhibiting disability or death from endogenous or pharmacologic TPA toxicity due to thrombosis in a lung and a method of inhibiting disability or death from endogenous or pharmacologic TPA mediated respiratory hemorrhage or edema comprising administering an anti-SerpinF2 antibody or fragment thereof. The specification teaches that the term “antibody” encompasses a SerpinF2-binding agent or molecule can include, among other molecules, antibodies (polyclonal or monoclonal). The term “antibody” (Ab) or “monoclonal antibody” (MAb) is meant to include intact molecules as well as antibody fragments (such as, for example, Fv, Fab and F(ab)2 fragments), single chain antigen-binding proteins, “humanized” antibodies, and chimeric antibodies which are capable of specifically binding to SerpinF2. Fab and F(ab')2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding of an intact antibody. The specification teaches that the term antibody encompasses antibodies capable of binding to both human and nonhuman circulating SerpinF2 and nonhuman fibrin crosslinked SerpinF2. Thus, the term “SerpinF2 antibody” encompasses a broad genus of antibodies. The genus of fragments encompassed by the claims is broader still. The specification provides a single example of administration of an anti-SerpinF2 antibody that is not fully described with amino acid sequences for CDRs or variable regions (See pages 18-20). However, the claims encompass all possible antibodies or fragments thereof that reduce SerpinF2 activity or concentration. The broadest reasonable interpretation of the claims is that any anti-SerpinF2 antibody of fragment thereof is capable of being used in the method of the instant invention. The specification provides no guidance regarding the structural binding that must be present for the antibodies to be capable of these required functions. Thus, the antibodies described by the instant specification have no correlation between their structure and their function, and the specification provides insufficient written description to support the genus encompassed by the claims. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "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." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan could not envision the specific antibody variable regions/CDRs and binding specificity that would be able to bind to SerpinF2, while inhibiting disability or death from TPA toxicity or TPA mediated respiratory hemorrhage or edema. The specification describes the parent protein from which the specific antigen is derived, but provides no description of the specific antigen region, and does not describe how binding of an antibody to any specific antigen would result in inhibition or blocking of SerpinF2 activity or concentration. The instant specification also provides no information regarding the sequences or other structures that are required to produce the required SerpinF2 antibody having the function of inhibiting disability or death from pharmacologic or endogenous TPA toxicity or TPA mediated neurologic hemorrhage or edema. It is possible that an antibody could bind to the SerpinF2 protein, but not result in SerpinF2 inhibition, or in inhibiting disability or death from TPA toxicity or TPA mediated neurologic hemorrhage or edema, as they may not affect conformation, protein binding, or other aspects of SerpinF2 function. Without demonstration that any antibody that binds to SerpinF2 would result in neutralization of SerpinF2 activity and concentration and the required inhibiting disability or death from TPA toxicity or TPA mediated neurologic hemorrhage or edema, one of ordinary skill in the art could not predict the potential binding and neutralizing capability of any given antibody or fragment thereof. Antibodies are capable of binding to any number of possible epitopes on a given protein, and not all of those interactions will result in any particular binding specificity or lost activity for the antigen protein. The disclosure fails to describe the common attributes or characteristics that identify the broad array of antibodies that are contained within the genus, and because the genus may be so highly variant, the examples provided, as well as the generic term of "antibody", is insufficient to describe the genus, even when considered in light of the general knowledge in the art. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus that the applicant was not in possession of the claimed genus. Therefore, the antibodies encompassed by the claims do not meet the written description provision of 35 USC 112, first paragraph.
The functional characteristics of antibodies including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. Mariuzza (Annu. Rev. Biophys. Biophys. Chem., 16: 139-159, 1987) reviews the structural basis of antigen-antibody recognition and teach that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure that fully comprises six CDRs, three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of the antibody's antigen-binding specificity. In view of Mariuzza, it is apparent that antibodies having less than all six CDRs that form the antigen binding site of a conventional antibody in their proper context of heavy and light chain variable domains do not describe the particularly identifying structural feature of the antibody that correlates with the antibody's ability to bind antigen.
Absent a description of the at least minimal structural features correlating with a functional ability to function in the claimed method(s) which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be mutated/varied such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed.
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, in a series of experiments involving a monoclonal antibody to Legionella pneumophilia serotype 1, McCarthy et al. (J. Immunol. Methods, 251(1-2): 137-149, 2001) demonstrated that a single CDR3 substitution of tyrosine to serine at position 95 resulted in the total loss of antigen recognition in an ELISA. Lin et al. (African Journal of Biotechnology, 10(79):18294-18302, 2011) teach that a single amino acid substitution in the VL CDR3 of an anti-avian infectious bronchitis virus (IBV) single-chain antibody (ZL.80) may abrogate binding. For example, at Figure 3, Lin et al. demonstrate that replacing either the Cys105 or Asp106 residue in the VL CDR3 of ZL.80 with an alanine residue reduces binding to near negative control levels. Lin et al. also teach that some single amino acid substitutions in the VL CDR3 of ZL.80 may significantly improve binding. For example, replacing the Val108 residue in the VL CDR3 of ZL.80 with a tyrosine residue results in a 12.9-fold increase in affinity compared to parental ZL.80. Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus comprising the claimed CDR sequences may be combined such that the resultant antibody possesses an antigen-binding site capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed.
The diversity of antibodies binding a single antigen is discussed by Ferrara et al. (mABs, 2015; 7(1): 32-41). Ferrara et al. teach that generation of antibodies to a single antigen using two rounds of phage display results in an antibody library comprising 105-106 antibodies (See page 36). Ferrara et al. teach that there is substantial variation in the genus of antibodies that bind a single antigen, on the order of hundreds of different sequences and states “The number of different HCDR3s selected against the test antigens ranges from 74 to 460, with the actual number of different antibodies likely to be significantly higher when different VL chains and additional VH mutations are taken into account” (See page 36). Given that Ferrara et al. teach that a single antigen can have hundreds of thousands of antibodies that bind, each of which can comprise antibodies that are structurally distinct from the SerpinF2 antibody disclosed, one of skill in the art would not conclude that the single antibody disclosed is representative of the genus.
The claims encompass a genus of antibodies that have specific required functions. The specification does not disclose specific species by amino acid sequence or other structure, and does not provide any guidance as to what specific structures or sequences are required for the claimed binding affinity and activity. Therefore, neither the art nor the specification provides a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
The specification does not describe the particular structural features of the genus of anti-SerpinF2 antibodies that would perform the functions of the instant method. The specification describes a suggested method for identifying an antibody that would accomplish the claimed functions. However, the skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
The MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The Guidelines for Examination of Patent Applications under the 35 USC §112 paragraph 1, “Revision 1” of Written Description Requirement (66 FR 1099-1111, March 25, 2008) state, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention (ld. At 1104). Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Consequently, the method of inhibiting disability or death from endogenous or pharmacologic TPA toxicity due to thrombosis in a lung and a method of treating respiratory hemorrhage or edema comprising administering an anti-SerpinF2 antibody or fragment thereof does not meet the written description provision of 35 U.S.C. 112(a) or 112 (pre-AIA ) first paragraph. The specification has not sufficiently described the genus of antibodies encompassed by the claims. The treatment of a subject with stroke with a single SerpinF2 antibody cannot be deemed to be predicative of a subject with the broad genus of anti-SerpinF2 antibodies because the genus is highly variant. Therefore, the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claims 58-63 and 65-71 are included in this rejection because they depend from claims 57 and 64 and thereby incorporate the above described written description deficiency and fail to remedy that deficiency.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 57-71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6, 8, 11, 15, 30-39, and 43-45 of U.S. Patent No. 11236176 (reference application) in view of Desciak et al (Perioperative Pulmonary Embolism: Diagnosis and Anesthetic Management, https://doi.org/10.1016/j.jclinane.2010.06.011) as evidenced by Merriam-Webster Dictionary (Ischemia, retrieved from https://www.merriam-webster.com/dictionary/ischemia#:~:text=is%2D%CB%88k%C4%93%2Dm%C4%93%2D%C9%99,ischemic%20adjective). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of both applications cover methods using the same active steps to address conditions with the same mechanistic causes.
Regarding instant claims 57-59 and 64-66, reference claims 6, 30, and 30 recite the same active steps of determining that a patient has or is at risk for TPA toxicity (due to an ischemic event of at least 3 hours) and then administering a composition comprising a SERPINF2 (α2AP) inhibitor to treat or inhibit disability or disease from endogenous or pharmacologic TPA toxicity due to ischemia from stroke in a patient in need thereof.
The reference application does not teach the methods relating to TPA-mediated respiratory hemorrhage or edema.
However, Desciak et al teach that abnormalities in respiratory function and pulmonary gas exchange are some of the first changes seen when venous emboli lodge in the lungs. They have been attributed to an increase in alveolar dead space, which may be consequences of the physical obstruction to blood flow caused by the emboli themselves (see section 3.1). Note that ischemia is a deficient supply of blood to a body part that is due to obstruction of the inflow of arterial blood as evidenced by Merriam-Webster Dictionary. As blood flow is shunted away from the obstructed pulmonary arteries (PAs), it then causes overperfusion of the rest of the lung tissue, leading to edema, loss of surfactant, and alveolar hemorrhage (see section 3.1 of Desciak et al).
Therefore, one of ordinary skill in the art would have found it obvious that breaking up the thrombus in the lung would decrease the overperfusion to the rest of the lung, thereby treating/inhibiting disability or disease from respiratory hemorrhage or edema by reducing the mechanisms responsible for the respiratory hemorrhage or edema. Furthermore, one of ordinary skill in the art would have found it obvious that evidence of a thrombus (thrombosis), such as a thrombus caused by the well-known condition of pulmonary embolisms, in a lung is evidence of respiratory symptoms indicative of lung damage.
The only difference between the instant claims and those of the reference patent is the event initiating TPA exposure: a lung thrombus or ischemia from stroke. Beyond that, the patient population for administering the anti-SERPINF2 antibody according to the otherwise identical methods is people determined to be at risk for TPA-mediated toxicity. Thereby, one of ordinary skill in the art would have found the reference application to be obvious to apply to a patient at risk of TPA-toxicity either due to pharmacological administration or endogenous exposure in response to some biological event. The reference application claims do not require concurrent administration of TPA and are therefore held to read upon a method(s) excluding concurrent administration of TPA. As such, the enumerated claims of the reference application are held to make obvious the instant claims
Regarding claims 60, 67, and 71 reference claims 11, 32, and 35 recite that the TPA was previously administered to the patient within 48 hours.
Therefore, because the SERPINF2 inhibitor is being administered for the same purpose, minimizing results of TPA toxicity, one of ordinary skill in the art would have found it obvious to employ the active steps of the methods of instant claims 57 and 64 where TPA was previously administered to the patient within 48 hours (and 3 hours after the event preceding TPA (endogenous or pharmacologic) exposure (such as ischemia or thrombosis) with a reasonable expectation of success because the mechanistic action of the SERPINF2 inhibitor in the instant and reference applications is the same.
Regarding claims 61 and 68-70, reference claims 15, 33, 36, and 43-45 teach that a dose of 28-91 nanomoles/kg and a dose of 17-50 nanomoles/kg of the SERPINF2 inhibitor are effective doses for achieving the effects of treating or inhibiting the effects of TPA-mediated toxicity. Therefore, because the SERPINF2 inhibitor is being administered for the same purpose, minimizing results of TPA toxicity, one of ordinary skill in the art would have found it obvious to employ the active steps of the methods of instant claims 57 and 64 with the doses of 91 nanomoles/kg and a dose of 17-50 nanomoles/kg of the SERPINF2 inhibitor as recited in reference claims 15, 33, 36, and 43-45 because the reference application teaches that these are effective doses that yield predictable and desirable results for mitigating the damaging effects from TPA toxicity.
Applicant’s Arguments and Responses
A. Applicant argues for withdrawal of the rejections of the claims under 35 USC 112(a) for lack of written description of the genus of anti-SERPINF2 antibodies because the claims are not directed towards the genus of antibodies, but are instead directed towards one or more uses of said genus of antibodies, which Applicant alleges are described by the prior art. Applicant argues the description of a genus of antibodies is not proper grounds for rejection where the claims are directed towards a method of using the claimed genus and cites to PTAB decision to support this position.
Response: These arguments are found unpersuasive for the following reasons. The claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
The claims require administering an antibody that binds SERPINF2 or fragment thereof that reduces SERPINF2 activity. The specification does not describe which amino acid residues of the administered antibody are responsible for the functions claimed. Rather, the specification states that these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. Although the specification provides one example of administration of an anti-SERPINF2 antibody, it fails to disclose the structures common to all members of the genus of antibodies encompassed by the broad definition provided by applicant. The specification does not disclose the structure of all of the claimed variant agents and fails to disclose which regions of the agents are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP §2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that reduce SerpinF2 activity against plasmin, i.e. the required starting materials for the claims, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face. Unlike Applicant’s citation to Ex Parte Jayakrishna Ambati, Rochester is precedential and binding upon cases thereafter, not solely for the case it was issued with respect to. Therefore, this citation is insufficient to support withdrawal of the rejections for lack of written description at this time.
The specification provides one example of administration of an antibody (not providing the structure of said antibody) that binds to SERPINF2 as broadly claimed. The specification does not describe the structure of the full genus of antibodies responsible for each of the functions claimed. It is noted that the specification cites and incorporates references which describe a genus of anti-SERPINF2 antibodies, but does not support that these antibodies would all function in the method as claimed. The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When 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). Here, the administered antibody is claimed only by function, i.e. binding to SERPINF2 and reducing its activity against plasmin.
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of antibodies nor guidance as to which of the myriad of molecules encompassed by the claimed antibodies would meet the limitations of the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of antibodies encompassed by the claimed invention.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “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.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of the genus of claimed agents to be used in the instant method, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Therefore, the rejections of the claims under 35 USC 112(a) are maintained. The rejection of record is not viewed as confusing enablement and written description as the rejection clearly stands on Applicant’s failure to disclose a representative number of antibodies which bind SERPINF2 and reduce its activity against plasmin as claimed where a search of the prior art fails to provide adequate written description of the genus claimed.
It is noted that Applicant alleges this genus is well known in the art. However, it is well settled that the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I).
As noted, there is significant diversity in the genus of antibodies binding a single epitope. The disclosure of 10 antibodies is not sufficiently representative of the genus of antibodies and fragments thereof claimed and there remains no demonstrated structure-function correlation which would provide description to the claimed genus. The argument that the disclosure of Bute et al provides the requisite description by teaching antibodies that functioning the method of Butte et al is unpersuasive unless Applicant is stating that the method of Butte et al is an obvious variant of the claimed method. Assuming that Applicant is not conceding this point, there is a presumption that the method of Butte et al is different than the claimed method entailing different requirements for description of the genus of antibodies compatible for use in the method.
Therefore, the rejections of record as they appear in this Office Action are maintained at this time.
B. Applicant offers no arguments for withdrawal of the rejections for non-statutory double patenting.
Response: Applicant’s attention is respectfully directed to M.P.E.P. § 804(I)(B)(1), which states: “A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional.” “As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Replies with an omission should be treated as provided in MPEP § 714.03.Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner.” See MPEP § 804.02, subsection VI, for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995. (emphasis added). Accordingly, the rejection is maintained and is expressly not held in abeyance.
Conclusion
Note that the prior art cited in the rejections of record as they appear in the previous Office Action is deemed to be the closest prior art. In summary, Butte et al (a2-Antiplasmin causes Thrombi to Resist Fibrinolysis Induced by Tissue Plasminogen Activator in Experimental Pulmonary Embolism, https://doi.org/10.1161/01.CIR.95.7.1886) teach an animal model where TPA and an inhibitory anti-SERPINF2 antibody (called an α2AP antibody) is administered leading to increased lysis of thrombi and no consumption of fibrinogen (see for example the abstract, paragraphs 1-3 of the introduction, and the Methods and Discussion sections). Gravanis et al (Tissue-type plasminogen activator as a therapeutic target in stroke. Expert Opin Ther Targets. 2008 Feb;12(2):159-70) teach that TPA can result in toxicity which may result in hemorrhage, which limits the use of TPA. However, there is not clear teaching and/or motivating administration of an anti-SERPINF2 antibody to a subject determined to be at risk of TPA toxicity due to prolonged thrombosis in a lung of a patient in order to inhibit disability or death from endogenous or pharmacologic TPA-mediated respiratory hemorrhage or edema. A showing that administering an anti-SERPINF2 antibody does not increase fibrinogen consumption is the closest teaching of the prior art, but is not sufficient to motivate the method instantly claimed by claims 57-71. Therefore, the instant claims 57-71 are deemed to be free from the prior art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Nassar et al (tPA Regulates Pulmonary Vascular Activity Through NMDA Receptors, Am J Physiol Lung Cell Mol Physiol. 2011 Sep;301(3):L307-14) teach that tissue-type plasminogen activator (tPA) is a fibrinolytic enzyme used in the treatment of arterial and venous thromboembolic diseases. The beneficial effects of tPA in managing acute coronary syndromes are clear. In contrast, the beneficial effects of tPA in the treatment of stroke are less striking, and its effectiveness in the management of pulmonary embolism is uncertain. tPA regulates the contractility of smooth muscle cells in isolated blood vessels and cerebrovascular contractility and cerebral blood flow. tPA also increases the permeability of the blood-brain barrier (BBB). Prior studies also indicate that the effect of tPA on cerebrovascular contractility and permeability contribute to its hemorrhagic and neurotoxic side effects and that neutralizing either or both of these extra fibrinolytic effects improves neurological outcome after thrombolytic therapy for acute thromboembolic stroke. This strategy is based on the finding that tPA is an “allosteric” enzyme that is regulated through its PAI-1 docking site. Similar effects may occur in the lung (see the Introduction).
US 6114506 A teaches that a patient treated according to the preferred embodiment will, therefore, receive an intravenously injected bolus of the .alpha.2AP-binding molecule in combination with an intravenously injected bolus of the thrombolytic agent. This preferred treatment minimizes the amount of t-PA required for thrombolysis, thus reducing the extent of fibrinogen breakdown and lessening any tendency for general hemorrhage. Importantly, the use of the preferred treatment results in the dissolution of the occluding thrombus at a rate which greatly exceeds the rate of thrombus dissolution when either the .alpha.2AP-binding molecule or the thrombolytic agent is provided by infusion alone. Additionally, the risk of re-occlusion is substantially reduced.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678