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 .
Priority
This application is a national stage application under 35 U.S.C. § 371 of
International Application No. PCT/EP2021/058240, filed 03/30/2021, which claims the priority benefit of European Patent Application No. 20167256.5, filed 03/31/2020 and European Patent Application No. 21163417.5, filed 03/18/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on dates 01/27/2023, 10/03/2023, 11/09/2023, 12/14/2023, 02/06/2024, 03/04/2024, 05/29/2024, 08/22/2024, 02/19/2025, 05/19/2025, and 08/27/2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Applicant has submitted jumbo information disclosure statements without
specifically pointing out where relevant material can be found in each of the references.
As a result, the examiner has considered said information disclosure statements to the
extent permitted by the allotted time for such consideration and consistent with the MPEP.
Election/Restriction
Applicant's election without traverse of viral pneumonia, and lungs as an organ with local inflammatory condition, and the election of {3-[1-(2-nitrophenyl)-lH-pyrrol-2-yl]-allylidene}-aminoguanidine acetate as the compound of formula I in the reply filed 09/09/2025 is acknowledged.
Claims 99-118 are pending. Claim 108 been amended. Claims 106-107, 113, and 115 have been withdrawn from further consideration as being drawn to a non-elected species. Claims 99-105, 108-112, 114 and 116-118 are examined herein insofar as they read on the elected species.
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.
Claim 109 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a viral disease, does not reasonably provide enablement for reduced time to recovery from every form of said disease or disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
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 In re Wands, 8 USPQ2d 1400 (1988), the factors to be considered in determining whether a disclosure meets the enablement requirement are as follows:
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
7. The quantity of experimentation needed, and
8. The level of skill in the art
The Nature of the Invention and Breadth of the Claims
Claim 109 is dependent on claim 99 and is drawn to a method of treating a viral disease or disorder, by administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of formula (I), wherein said treatment reduces the time to recovery.
The State of the Prior Art and the Predictability or lack thereof in the art
“Historically, infectious diseases, particularly due to viruses, have been one of the most important contributors to human morbidity and mortality. They account for a large proportion of death and disability worldwide, and remain in certain regions the most important cause of ill health. The burden of viral diseases and disorders is illustrated by the recent outbreak of coronavirus disease 2019 (COVID-19)” (Specification page 1, lines 9-13). The treatment of COVID-19, viral diseases and disorders and inflammation by administering a compound of formula I or AP1189 is also disclosed (specification page 3 line 21 through page 4, line 6).
However, none of the prior art compounds are reported to completely prevent the onset of any or every viral disease or disorder by administering a compound of formula I or AP1189.
It is noted that pharmacological activity in general is a very unpredictable area. In cases involving physiological activity, such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Guidance Present and Presence/Absence of Working Examples
The only guidance disclosed by the specification regarding reduced recovery of a viral disease is found on page 51 of the specification:
“Results - initial open label part of the study
6 patients referred to hospital with Covid-19 induced pulmonary insufficiency received
once daily oral dosing of 100 mg AP1189 as add-on to standard therapy (oxygen on
nasal catheter with flow between 2-5 LO2/min).
In these patients, the compound was found to be safe and well tolerated, and the
patients were discharged between day 3 and 9 of treatment as none of them developed
a need for more intensive pulmonary support. This indicated a potential of the
compound to reduce the time to respiratory recovery (i.e. time to normalization of
oxygen saturation on ambient air).”
The specification does not provide any guidance for determining which particular patient population would be susceptible to developing a viral disease. Also lacking are data showing that the compounds are capable of reducing the time to recovery of all or every viral disease. Also lacking is establishing whether recovery from a viral disease is when the virus is eliminated from the body or when a subject no longer shows symptoms.
The quantity of experimentation needed, and level of skill in the art
In order to treat every or all virus types one would need to precisely identify those subjects with the disease or disorder who are likely to respond to treatment, administer the claimed invention, and demonstrate that administration directly resulted in the subject overcoming the disease or disorder. One skilled in the art would conclude that the guidance in the specification would not have taught one skilled in the art how to treat every or all virus types using the compounds of formula (I), because there is no guidance for how to select a patient population and no evidence that the claimed compounds can broadly treat every virus type. Given the lack of guidance in the specification and the lack of success in the prior art, one skilled in the art would find that preventing the claimed diseases or disorders would require experimentation that is unduly burdensome. This rejection may be overcome by cancelling claim 109, or specifying what constitutes recovery from a viral disease or disorder from line 2 of claim 109.
Claim Rejections - 35 USC § 112
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 101, 105, 108-109, 111-112, and 116-118 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.
Regarding claims 101, 105, 108, 111-112, 116-118, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 105 and 118, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 99-105, 108-112, 114 and 116-118 are rejected under 35 U.S.C. 103 as being unpatentable over Boman (U.S. PAT. 8,058,306 B2).
The instant claims are directed to a method of treating a viral disease or disorder comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) ({3-[ 1-(2-nitrophenyl)-lH-pyrrol-2-yl ]-allylidene}-aminoguanidine).
Boman et al. teaches a phenyl pyrrole aminoguanidine acetate derivative of general formula I as compound 19, {3-[ 1-(2-nitrophenyl)-lH-pyrrol-2-yl ]-allylidene}amino guanidinium, CAS registry number 959850-73-8, “shows the synthetic route to compound 2 of the invention, [1-(2-Nitrophenyl)-1H-pyrrol-2-yl-allylideneamino]guanidinium acetate (see FIG. 1D, structure no. 19).” [sic] (col. 3, lines 65-66). Boman also teaches “In a further aspect the present invention relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.” (col. 3, lines 26-30). Bowman teaches administration of a compound of formula I for the treatment of a systemic disease including inflammatory diseases and central nervous system diseases related to inflammation including viral infections (col. 21, lines 3-31). See MPEP 2131 Boman also teaches that compounds of the invention may be converted to their active acid addition salts with organic acids including acetic acid (col. 11, lines 26-32). Boman also discloses that the compounds of the invention are agonists or antagonists capable of binding to MC receptors MC1 and MC3 (col. 18, lines 9-15). Boman also discloses that administration of a compound of formula I is used for the treatment of inflammation related to any origin including inflammation caused by a virus including AIDS (col. 23, lines 17-23). Boman also teaches treatments to inhibit acute renal failure in example 9 (col. 35, lines 6-20 and example 9, col. 36). Boman teaches that compounds of formula I are useful for the treatment of inflammation related to interleukin 6 (col. 19 line 56 – col. 20 line 3). Boman discloses compound 2 is widely distributed to tissues (col. 46, lines 49-57). Boman also teaches example 12 wherein compounds of the invention are administered via oral gavage, intravenous and subcutaneous injection once or twice daily (col. 39, lines 57-62).
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(Boman’s compound 19)
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to use Boman’s disclosed compound 19 to treat a viral disease or disorder by daily administration to a subject in need thereof because Boman disclosed the use of phenyl pyrrole aminoguanidine derivatives for the treatment of diseases associated with the melanocortin receptors which are related to inflammation and further disclosed the mean concentration in plasma following intravenous administration, intravenous pharmacokinetics, and oral bioavailability of compound 19 in example 13, figures 1D, 2, 7, and 10 including a synthesis scheme in example 1 using acetic acid. A skilled artisan would have been motivated to select structure 19 for administration to a subject with a viral disease or disorder due to a combination of an already disclosed synthesis scheme of structure 19, available plasma concentration data from administration to subjects and disclosure that compound 2 is widely distributed to tissues.
Boman’s compound of {3-[1-(2-nitrophenyl)-lH-pyrrol-2-yl]-allylidene}-amino guanidinium, taught as structure 19 satisfies the structural limitations of formula I of the instant claims where R1 is NO2, R2-R7 is H, n is 1.
A person of ordinary skill in the art would have been motivated to select the compound of structure 19, for use in a pharmaceutical composition for daily administration to a subject with a viral disease or disorder because of the disclosures of Boman regarding wide systemic distribution into tissues by structure 19 and the teachings that positive effects seen where inflammation is caused by viral infection. A person of ordinary skill would have further been motivated to use Boman’s teachings of structure 19 because of the ability of compound 2 (structure 19) to become widely distributed into tissues and therefore would have given the skilled artisan a reasonable expectation of success in treating systemic inflammation caused by viruses.
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.
Claim 99 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 26-27 of U.S. Patent No. 12,239,631 B2 (to Boesen) in view of Boman (U.S. Patent No. 8,058,306 B2).
Instant claim 99 is drawn to a method of treating a viral disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of formula (I).
Boesen et al. recites the compound of formula I (N-{3-[1-(2-nitrophenyl)lH-pyrrol-2-yl]-allylidene}-aminoguanidine) in claim 27, shown below. Boesen’s compound of formula I satisfies the structural limitations of instant claim 99
However Boesen does not teach administering the compound of formula I for the treatment of a viral infection in a subject.
Boman teaches phenyl pyrrole aminoguanidine derivatives for the treatment of diseases associated with the melanocortin receptors or related systems (Abstract). Boman discloses an aspect of the invention which includes treatment for viral infections in the central nervous system (col. 21, lines 28-32). Boman also teaches example 19 as a phenyl pyrrole aminoguanidine derivative (fig. 1d).
It would have been prima facie obvious to one of ordinary skill to combine the teachings of Boman’s compound derivative of formula I as structure 19 ({3-[1-(2-nitrophenyl)lH-pyrrol-2-yl]-allylidene}-aminoguanidine), with Boesen’s disclosure of formula I (N-{3-[1-(2-nitrophenyl)lH-pyrrol-2-yl]-allylidene}-aminoguanidine) to treat a subject with a viral disease or disorder because Boesen’s formula I is equivalent to Boman’s compound of structure 19 as a de-protonated version and would therefore be expected to treat the viral infections disclosed by Boman. See MPEP 2112.
A person of ordinary skill in the art would have had a reasonable expectation of success in treating a subject with a viral disease or disorder with Boesen’s compound of formula I when combined with Boman’s teachings of administering a compound of formula I (structure 19) for the treatment of diseases associated with the melanocortin receptors or related systems, which would include viral infections in the central nervous system..
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Applicants formula I (Left) Boesen’s formula I (Right)
Claim 99 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 15 and 17 of U.S. Patent No. 12,303,489 B2 (to Jonassen) in view of Boman (U.S. Patent No. 8,058,306 B2).
Instant claim 99 is drawn to a method of treating a viral disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of formula (I).
Jonassen et al teach the compound of formula II (N-{3-[1-(2-nitrophenyl)lH-pyrrol-2-yl]-allylidene}-aminoguanidine) in claims 9 and 17 (shown below). Jonassen’s compound of formula II satisfies the limitations of claim 99 of the instant claims where R1 is NO2, R2-R7 is H, n is 1.
However Jonassen does not explicitly teach administering the compound of formula I for the treatment of a viral infection in a subject.
Boman teaches phenyl pyrrole aminoguanidine derivatives for the treatment of diseases associated with the melanocortin receptors or related systems (Abstract). Boman discloses an aspect of the invention which includes treatment for viral infections in the central nervous system (col. 21, lines 28-32). Boman also teaches example 19 as a phenyl pyrrole aminoguanidine derivative (fig. 1d).
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Boman’s compound of structure 19 ({3-[1-(2-nitrophenyl)lH-pyrrol-2-yl]-allylidene}-aminoguanidine) administered for the treatment of a viral infection in a subject with Jonassen’s disclosure of formula II for the treatment of a subject with a viral disease or disorder because Jonassen’s formula II is equivalent to Boman’s compound of structure 19 as a de-protonated version and would therefore be expected to treat viral infections as disclosed by Boman because of the equivalent chemical structures of both compounds. See MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof.
A person of ordinary skill would have had a reasonable expectation of success in treating a subject with a viral disease or disorder by administering Jonassen’s compound of formula II to a subject in need thereof following Boman’s teachings of administering a compound of formula I for the treatment of viral conditions with the compound of example 19, a phenyl pyrrole aminoguanidine derivative because Boman already disclosed working examples of administering phenyl pyrrole aminoguanidine derivatives for the treatment of diseases associated with the melanocortin receptors or related systems, which would include inflammation associated with a viral infection. See MPEP 2144.09.
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Applicants formula I (Left) Jonassen’s formula II (Right)
Conclusion
Claims 101, 105, 108, 111-112, and 116-118 are rejected. No claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623