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 .
Claims 1-4 are pending.
Specification
The disclosure is objected to because of the following informalities:
The title of the invention is not descriptive because it is directed generally to any type of formulation for treatment of stroke, but the claimed composition is limited to comprising an endothelin-B receptor analog. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “PHARMACEUTICAL FORMULATION FOR TREATMENT OF CEREBRAL STROKE COMPRISING AN ENDOTHELIN-B RECEPTOR ANALOG”.
Appropriate correction is required.
Claim Objections
Claims 1-4 are objected to because of the following informalities:
In claim 1, line 2, there should be a space between “0.00001” and “mg/kg”.
In claim 1, line 3, there should be a space between “0.0015” and “mg/kg”.
In each of claim 2 (line 2) and claim 3 (line 1), the recitation of “but not limited to” is missing a verb; e.g., “but is not limited to”.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 3 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 2 is indefinite for two reasons:
---The claim states that “said endothelin-B receptor analog” of parent claim 1, which is a recitation of a singular analog, “includes but not limited to” a group of compounds, which encompasses multiple compounds. In this regard the claim could be rendered definite if, for example, parent claim 1 was amended to recite “one or more endothelin-B receptor analogs” and claim 2 was amended to recite wherein “said one or more endothelin-B receptor analogs includes but are not limited to…”
---Claim 2 is also indefinite because the recited group of analogs is missing a conjunction, and thus it is unclear whether “and” or “or” is intended.
Claim 3 is indefinite for the same two reasons as claim 2, but with respect to “said drug” encompasses multiple drugs and the recited group lacking a conjunction..
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
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 1-3 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 invention is directed to a pharmaceutical formulation for treatment of cerebral stroke comprising two components: (1) an endothelin-B (ETB) receptor analog, in a dose in a range of 0.00001 mg/kg to 1 mg/kg; and (2) a drug in a dose in the range of 0.0015 g/kg to 5 g/kg. The specification teaches that the basis of the invention is “a synergistic effect of at least two pharmaceutically active ingredients” (¶ 14, published application). The specification teaches that the combination “increases overall efficacy of the formulation” over compositions comprising a single drug (¶ 7-8).
The claims are genus claims because each component of the formulation is directed to a genus of compounds acting as a therapeutic for stroke, and acting synergistically. Each genus is highly variant because there are large structural differences between genus members. The specification places no limit on the structure of either the ETB receptor analog or the drug; therefore each encompasses a molecule of any structure: peptides, polypeptides, nucleic acids, antibodies, carbohydrates, oligosaccharides, other polymers, lipids, small organic compounds, inorganic compounds and other molecules. Furthermore, each of these categories itself constitutes an entire subgenus of molecules having a variety of different structures; e.g., a subgenus of peptides having different amino acid structures.
With respect to ETB analogs, from the specification, it is clear that Applicant has possession of the compounds listed in claim 2, each of which was known in the prior art as an agonist of the ETB receptor: sovateltide (also known as IRL-1620), BQ-3020, [Ala1,3,11,15]-endothelin, sarafotoxin S6c and endothelin-3. Furthermore, each is a peptide compound. Sovateltide, BQ-3020 and [Ala1,3,11,15]-endothelin are related in structure in that they are derived from the peptide endothelin-1. The specification does not provide any examples of other structures that act as a ETB receptor analog, i.e., an agonist of the ETB receptor, or examples of the many other types of compounds encompassed by the claims, e.g., polypeptides, nucleic acids, antibodies, carbohydrates, oligosaccharides, other polymers, lipids, small organic compounds, inorganic compounds and other molecules.
With respect to the “drug in a dosing range of 0.0015 g/kg-5 g/kg”, which per the specific is to work synergistically with the ETB receptor analog, the specification provides only two examples, mannitol and citicoline (¶ 16, 36, 50), which are also employed in the working examples. These are each small organic molecules, but are otherwise unrelated in structure, with mannitol being a sugar alcohol, and citicholine, also known as CDP-choline, being a precursor of phosphatidylcholine. The specification does not describe how the structure of each is related to the synergism observed in treatment of stroke demonstrated in the working examples. No other examples of structures having such a synergistic effect when administered a dose in the specified range is provided.
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 structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. In the instant case, the specification fails to provide sufficient descriptive information, such as definitive structural or functional features, or critical conserved regions, corresponding in scope to the structures encompassed by the ETB receptor analog or the synergistic drug. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. Thus, no identifying characteristics or properties of the instant polypeptides are provided such that one of skill would be able to predictably identify the encompassed molecules as being identical to those instantly claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe each genus. Thus, Applicant was not in possession of each claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, 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). As discussed above, the skilled artisan cannot envision the detailed chemical structure of each genus, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. 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. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only a pharmaceutical formulation for treatment of cerebral stroke comprising two components: (1) an endothelin-B (ETB) receptor analog, in a dose in a range of 0.00001 mg/kg to 1 mg/kg; and wherein the analog is sovateltide, BQ-3020, [Ala1,3,11,15]-endothelin, sarafotoxin S6c or endothelin-3, and (2) a drug in a dose in the range of 0.0015 g/kg to 5 g/kg, and wherein the drug is mannitol or sovateltide, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is 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).
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 1-4 are rejected under 35 U.S.C. 103(a) as being unpatentable over U.S. Patent 8,623,823, published 1/7/14 (cited on the 6/28/23 IDS), and further in view of U.S. Patent 5,872,108, published 2/16/99. The earliest date to which the instant application claims priority is 6/28/23.
Claims 1-4 each encompass a pharmaceutical formulation for treatment of cerebral stroke comprising (i) an endothelin-B receptor analog in a dosing range of 0.00001 mg/kg to 1 mg/kg (which is equivalent to 0.01 µg/kg to 1 mg/kg), and wherein the analog is sovateltide; and (i) a drug in a dosing range of 0.0015 g/kg to 5 g/kg, and wherein the drug is citicholine. The compound sovateltide is also known as IRL-1620, as evidenced by Gulati et al (2021. CNS Drugs. 1: 85-104); see Abstract.
The ’823 patent teaches “pharmaceutical compositions comprising an ETB receptor agonist and a second therapeutic agent useful in the treatment of strokes” (col 9, lines 37-41). ‘823 further teaches that “for administration to a human in the treatment of stroke or other cerebrovascular accident, oral dosages of an ETB agonist, individually generally are about 0.005 to about 500 micrograms daily for an average adult patient (70 kg), typically one dose per day”. A dosage of 500 µg per 70 kg is 7.14 µg/kg, which is within the range encompassed by the instant claims. ‘823 further teaches that the second therapeutic agent can be citicholine (col 10, line 59 through col 11, line 11). The ‘823 patent further teaches that “The effective dosage range for each neuroprotective agent is known in the art, and the neuroprotective agent is administered to an individual in need thereof within such established ranges” (col 10, lines 12-16). ‘823 does not teach a specific dose of citicholine to be administered.
The ‘108 patent teaches a “method of reducing the extent of infarction, particularly cerebral infarction, subsequent to an ischemic event” by using citicoline (col 1, starting line 10). The ‘108 patent further teaches pharmaceutical medicaments comprising citicholine (col 3, starting line 20). ‘108 further teaches that the dose of citicholine is 100 – 2000 mg per day, with 500-1000 mg being preferred and 500 mg being most preferred (col 3, starting at line 26).
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 pharmaceutical formulation for treatment of cerebral stroke comprising IRL-1620 (sovateltide) and citicholine as taught by ‘823, and formulated at a dose of IRL-1620 taught by ‘823, for example 7.14 µg/kg, and modify such a composition to include citicholine at a dose taught by ‘108, for example the preferred dose of 500 mg. A dose of 500 mg of citicholine would be, for the average adult weight of 70 kg as taught by ‘823, 7.14 mg/kg, which is within the range recited by claim 1. The person of ordinary skill in the art would be motivated to make such a change because ‘823 teaches a pharmaceutical composition comprising IRL-1620 and citicholine, but does not teach the dose of citicholine to use in such a composition, and ‘108 provides the necessary missing information regarding an appropriate dosage of citicholine for treatment of stroke. A person of ordinary skill in the art would have had a reasonable expectation of success because making such a change merely requires formulating the citicholine to a dosage that is taught by the prior art to be effective. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Double Patenting
The nonstatutory double (NSDP) 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 NSDP 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 (TD) in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on NSDP 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 TD must be signed in compliance with 37 CFR 1.321(b).
The filing of a TD by itself is not a complete reply to a NSDP rejection. A complete reply requires that the TD 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 TD 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 (eTD) may be filled out completely online using web-screens. An eTD that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTDs, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 are rejected on the ground of nonstatutory double patenting as being unpatentable over either (1) claims 1-3, 9-11 and 15-18 of U.S. Patent No. 9,493,524, issued 11/15/16; or (2) claims 1-3, 9-11 and 16-19 of U.S. Patent 10,112,981, published 10/30/18, and each of which shares the same inventor with the instant application, and each further in view of U.S. Patent 5,872,108, published 2/16/99. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
Instant claims 1-4 encompass the subject matter described above in the section, “Claim Rejections - 35 USC § 103”.
The ‘981 patent issued from application 15/352,238, which claims priority as a continuation to application 14/149,785, from which the ‘524 patent issued.
The claims of each patent are directed to methods of treatment encompassing administration of N-Succinyl-[Glu9,Ala11,15] Endothelin-1 (which, like IRL-1620, is another name for sovateltide) and citicholine in a single pharmaceutical composition. Claim 1 of the ‘524 patent is directed to a “method of reducing damage to a brain cell caused by lack of blood supply or lack of oxygenation to the brain cell comprising administering a therapeutically effective amount of N-Succinyl-[Glu9,Ala11,15] Endothelin 1 to an individual in need thereof, wherein the administering comprises multiple dose administration of N-Succinyl-[Glu9,Ala11,15] Endothelin-1”, and claim 2 limits the method to one wherein a second therapeutic is administered. Claim 1 of ‘981 encompasses a method of treating stroke comprising administering multiple doses of a therapeutically effective amount of N-Succinyl-[Glu9,Ala11,15] Endothelin-1 to an individual in need thereof and further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of stroke. Dependent claims of each patent further require that the second therapeutic is citicoline (claim 9 of each patent) and that the N-Succinyl-[Glu9,Ala11,15] Endothelin-1 and the second therapeutic to be “administered in a single composition” (claim 11 of each patent). Dependent claims of each patent further require that the N-Succinyl-[Glu9,Ala11,15] Endothelin-1 is administered in “an amount of about 0.005 to about 500 micrograms per dose” (claim 15 of ‘524 and claim 16 of ‘981).
As such, the claims of each of ‘524 and ‘981 are directed to embodiments that are the same as the teachings of the ‘823 patent set forth above in the section “Claim Rejections - 35 USC § 103”. The claims of the ‘524 and ‘981 patents do not specify the dose of the citicoline to be administered.
The teachings of the ‘108 patent with respect to the dosages of citicholine for treatment of stroke are set forth above in the section “Claim Rejections - 35 USC § 103”.
It would have been obvious to modify the composition that is employed in the methods of the claims of ‘524 or ‘981 that comprises N-Succinyl-[Glu9,Ala11,15] Endothelin-1 (sovateltide) and citicoline in order to employ an amount of citicoline taught by the ‘108 patent, for the same reasons set forth in the section in the section “Claim Rejections - 35 USC § 103”.
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