DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-6 are pending.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/TR2021/051456, filed on December 22, 2021. This application also claims the benefits of International patent application PCTTR2020051347, filed on December 22, 2020.
Specification - Abstract
The abstract of the disclosure is objected to because it can be written more clearly.
An example of an amended abstract is as follows:
The present invention relates to a drug comprising a broad-spectrum serine protease inhibitor with a potent anti-viral and anti-inflammatory potential, nafamostat mesylate (NM), in an inhalation form for the infection treatment of SARS-CoV-2, Influenza A, Influenza B and NL63 viruses. Also provided is a method for preparing an inhalation formulation of the drug comprising NM for use in the prophylaxis of COVID-19-related mortality.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Examiner’s Note
According to MPEP § 2114, section II:
“‘[A]pparatus claims cover what a device is, not what a device does.’ Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990) (emphasis in original). A claim containing a ‘recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus’ if the prior art apparatus teaches all the structural limitations of the claim.”
This can also be translated to a product claim. A product claim covers what a product is, not what a product does. Therefore, a claim containing a recitation with respect to the manner in which a claimed product is intended to be employed does not differentiate the claimed product from a prior art product if the prior art product teaches all the structural limitations of the claim. As such, claims 1 and 2 of the instant application are both product claims that are directed towards a drug wherein the drug comprises a drug substance, nafamostat mesylate. Since claims 1 and 2 are product claims, the drug being used for an infection treatment of SARS-CoV-2, Influenza A, Influenza B, and NL63 viruses is non-limiting and is not considered when searching in the prior art.
Claim Rejections - 35 USC § 112
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 5 and 6 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 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 5 states that when the lyophilized powder formulations of nafamostat mesylate for an inhalation solution are diluted, the resulting solution has a pH that is adjusted to be within a range of 3.5 – 5.5. This limitation is not disclosed in the instant specification. Accordingly, claim 5 lacks adequate written description under 35 U.S.C. 112(a).
Claim 6 states that when the lyophilized powder formulations of nafamostat mesylate for an inhalation solution are diluted, the resulting solution has an osmolality that is adjusted to be within a range of 300-550 mOsm/kg. This limitation is not disclosed in the instant specification. Accordingly, claim 6 lacks adequate written description under 35 U.S.C. 112(a).
Claims 3-6 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims a drug comprising nafamostat mesylate (NM) in an inhalation form for the infection treatment of SARS-CoV-2, Influenza A, Influenza B and NL63 viruses. The present invention also claims a method for preparing an inhalation formulation of the drug comprising NM.
State of the prior art and the predictability or lack thereof in the art
Li (CN102836132A; published December 26, 2012) discloses a process (see Examples 1 through 10 in English-translated document) for preparing nafamostat mesylate in a lyophilized powder form for subsequent injectable administration. Li first describes preparing a pre-lyophilization solution by combining nafamostat mesylate with sterile water, mannitol, and a pH adjusting agent (para. 0026-0030 in English-translated document). Across the 10 examples, the amount of mannitol and the type of pH adjusting agent vary. The English-translations of the 10 specific formulation examples are provided on pg. 13-17 of the English-translated document of Li provided by Examiner. Li then specifies the steps necessary for converting the solution to the final lyophilized product (para. 0031-0034 in English-translated document). It is noted here that mannitol is considered an:
osmotic agent
(Keyrouz, S. G. et al. Variation in osmotic response to sustained mannitol administration. Neurocrit Care 2008, 9, 204-209.; 1st pg, abstract, “Background” section, 1st sentence),
a tonicity agent
(Mehmood, Y. et al. Excipients use in parenteral and lyophilized formulation development. Open Sci J Pharm Pharmacol 2015, 3, 19-27.; pg. 21, right col., subsection 3.1, last sentence), and
a freeze-drying agent
(Kumar, K. N. et al. Role of freeze-drying in the presence of mannitol on the echogenicity of echogenic liposomes. J. Acoust. Soc. Am. 2017, 142, 3670-3676.; pg. 3671, left col., section II, 2nd paragraph, 2nd sentence states: “Mannitol is widely used in lyophilization as a bulking agent because it promotes efficient freeze-drying.” Hence, mannitol is a freeze-drying agent.)
Therefore, Li not only discloses a drug comprising nafamostat mesylate (reads on instant claims 1-2), but also discloses a method of preparing the drug in a lyophilized powder form which comprises nafamostat mesylate, an osmotic agent, a freeze-drying agent, a tonicity agent, and a pH adjusting agent that adjusts the pH of the solution to the range of 3.0-4.5 (see para. 0027 in English-translated document of Li) (reads on instant claims 3-5).
Although the present claims recite a lyophilized powder of nafamostat mesylate for reconstitution to an inhalation solution, the prior art indicates that preparations of lyophilized therapeutic compounds are produced by the same process whether intended for intravenous injection or intranasal spray (see Example 1, para. 0032 in English-translated document of Ivashchenko: RU2738885C1; published December 18, 2020). Therefore, instant claims 1-5 are anticipated by Li and the claimed invention is predictable in view of the prior art.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in infectious disease and/or medicinal chemistry and would be familiar with standard methods for evaluating therapeutic efficacy.
The amount of direction or guidance present and quantity of experimentation necessary
The prior art (i.e., Li) does not disclose a lyophilized powder comprising nafamostat mesylate and the substances listed on pg. 15 of the clean version of the instant specification that are not mannitol, hydrochloric acid, and water. Herein, when referring to the instant specification, Examiner is referring to the clean version of the instant specification. Although the instant specification lists substances incorporated in formulation compositions (pg. 15) to develop the claimed lyophilized powder product, it does not disclose specific formulations (i.e., which subsets of the listed substances are used together and in what amounts).
In the absence of clear guidance, a person of ordinary skill in the art would require undue experimentation to determine a formulation composition comprising the substances on pg. 15 of the instant specification that is suitable for conversion into a lyophilized powder. As such, instant claims 3-6 fail to comply with the enablement requirement.
The presence or absence of working examples
In the instant case, the specification is not enabling because there are no specific examples of a formulation composition comprising the substances on pg. 15 of the instant specification that is suitable for conversion into a lyophilized powder as claimed in the present invention. As such, instant claims 3-6 fail to comply with the enablement requirement
The breadth of the claims
The claims are broad insofar as the instant claims recite a method of preparing a drug comprising nafamostat mesylate, a serine protease inhibitor, and various excipients.
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 3-6 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
According to MPEP § 2173.05(q):“Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112 second paragraph.”
Claim 3 is framed as a method of preparing the drug according to claim 2, yet no operative steps are provided. Hence, claim 3 is rendered indefinite.
Claims 4-6, which are dependent on claim 3, are also rejected for further requiring and/or reciting the indefinite limitation of claim 3.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 3-6 are rejected under 35 U.S.C. 101 because the claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ 678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966).
Claims 4-6, which are dependent on claim 3, are also rejected for further requiring and/or reciting improper process claim 3.
Note on 35 USC § 102 and § 103 Rejections
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 (i.e., changing from AIA to pre-AIA ) 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 § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Li et al. (Li) (CN102836132A; published December 26, 2012).
Li discloses a process (see Examples 1 through 10 in English-translated document) for preparing nafamostat mesylate in a lyophilized powder form for subsequent injectable administration. Li first describes preparing a pre-lyophilization solution by combining nafamostat mesylate with sterile water, mannitol, and a pH adjusting agent (para. 0026-0030 in English-translated document). Across the 10 examples, the amount of mannitol and the type of pH adjusting agent vary. The English-translations of the 10 specific formulation examples are provided on pg. 13-17 of the English-translated document of Li provided by Examiner. Li then specifies the steps necessary for converting the solution to the final lyophilized product (para. 0031-0034 in English-translated document). It is noted here that mannitol is considered an:
osmotic agent
(Keyrouz, S. G. et al. Variation in osmotic response to sustained mannitol administration. Neurocrit Care 2008, 9, 204-209.; 1st pg, abstract, “Background” section, 1st sentence),
a tonicity agent
(Mehmood, Y. et al. Excipients use in parenteral and lyophilized formulation development. Open Sci J Pharm Pharmacol 2015, 3, 19-27.; pg. 21, right col., subsection 3.1, last sentence), and
a freeze-drying agent
(Kumar, K. N. et al. Role of freeze-drying in the presence of mannitol on the echogenicity of echogenic liposomes. J. Acoust. Soc. Am. 2017, 142, 3670-3676.; pg. 3671, left col., section II, 2nd paragraph, 2nd sentence states: “Mannitol is widely used in lyophilization as a bulking agent because it promotes efficient freeze-drying.” Hence, mannitol is a freeze-drying agent.)
Therefore, Li not only discloses a drug comprising nafamostat mesylate (reads on instant claims 1-2), but also discloses a method of preparing the drug in a lyophilized powder form which comprises nafamostat mesylate, an osmotic agent, a freeze-drying agent, a tonicity agent, and a pH adjusting agent that adjusts the pH of the solution to the range of 3.0-4.5 (see para. 0027 in English-translated document of Li) (reads on instant claims 3-5).
Although the present claims recite a lyophilized powder of nafamostat mesylate for reconstitution to an inhalation solution, the prior art indicates that preparations of lyophilized therapeutic compounds are produced by the same process whether intended for intravenous injection or intranasal spray (see Example 1, para. 0032 in English-translated document of Ivashchenko: RU2738885C1; published December 18, 2020). Therefore, instant claims 1-5 are anticipated by Li.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 as of the effective filing date of the claimed invention(s) 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 as of the effective filing date of the later invention 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 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over:
Li et al. (Li) (CN102836132A; published December 26, 2012) and
Dhand (Dhand, R. How should aerosols be delivered during invasive mechanical ventilation? Respiratory Care 2017, 62, 1343-1367.)
The teachings of Li as they apply to claims 1-5 are as discussed in “Claim Rejections - 35 USC § 102” and incorporated herein.
Li does not disclose an ideal osmolality range of a drug solution for inhalation. Dhand is relied upon for this disclosure.
Dhand teaches that “[d]rug solutions for inhalation should have osmolality of 150–550 mOsm/Kg” (pg. 1359, left col., 1st paragraph, lines 2-4).
Therefore, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to take any of the lyophilized powders of nafamostat mesylate comprising a pH adjusting agent and mannitol (as disclosed by Li) and, upon reconstitution for inhalation, adjust the osmolality of the resulting solution to be within the range of 150-550 mOsm/kg (reads on instant claim 6). A POSITA would have been motivated to adjust the osmolality to be within this range as the prior art (i.e., Dhand) teaches that drug solutions for inhalation should have an osmolality within the range of 150-550 mOsm/Kg.
Additionally, since the invention as disclosed in instant claims 1-5 have been previously described in the prior art, a POSITA would have found it obvious to reproduce an already existing invention. Hence, instant claims 1-5 are also rendered obvious.
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 1-2 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1, 2, 6, 9, 10, 13, 17, 18, 20-23, 27, 29, 34, and 35 of U.S. Patent Application No. 17/608,452 (‘452).
Although the claims at issue are not identical, they are not patentably distinct from each other because there is overlap between the instant claims and the claim sets from the co-pending application.
Instant claims 1 and 2 are directed toward a drug comprising nafamostat mesylate in an inhalation form wherein the inhalation form is a lyophilized powder. The open-ended transitional term “comprising” implies that the drug of instant claims 1 and 2 can also comprise other components. See MPEP 2111.03 for details on transitional phrases.
Claim 29 of co-pending application ‘452 is directed towards a composition comprising nafamostat mesylate and oseltamivir. Claims 1, 2, 6, 9, 10, 13, 17, 18, 20-23, 27, 34, and 35 of ‘452 disclose a combination of nafamostat mesylate and oseltamivir. In the specification of the co-pending application, it states “[n]afamostat mesylate and oseltamivir may be co-formulated for simultaneous administration… The composition may be formulated as a… lyophilized mixture. The composition may be administered by any route known in the art. Non-limiting routes of administration include… inhalation” (pg. 11, lines 1-2 and lines 28-31).
Therefore, one of ordinary skill in the art would have found it prima facie obvious to prepare the composition of claim 29 in the co-pending application into a lyophilized form that is suitable for inhalation which reads on instant claims 1-2.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY H. MURRAY can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624