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 .
Status of the Application
The claims of 25 March 2024 are entered.
Claims 17 and 24-29 have been canceled. Claims 1-16 and 18-23 are pending and are being examined on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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 1-15 and 18-23 are 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 for the treatment of a Coronavirus, Orthopneumovirus, or an Othromyxovirus infection in a subject in need thereof by administering an effective amount of LTX-109, Arg-Phe(4-(1-Napthyl))-Arg-NH-CH2-CH2-Ph, LTX-7, or LTX-12, does not reasonably provide enablement for a method for the treatment of an enveloped virus infection in a subject thereof comprising administering an effective amount of a compound of formula (I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
“[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech Inc. v. Novo Nordisk 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997); In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); See also Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir. 1991); In re Fisher 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Further, in In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) the court stated:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman [230 USPQ 546, 547 (BdPatAppInt 1986)]. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredict-ability of the art, and (8) the breadth of the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention
The invention is drawn to a method of treating enveloped viral infections in a subject by administering a compound comprising a modified tripeptide.
Breadth of the Claims
The claims are broad with respect to the infection since it encompasses any enveloped virus as well as the compound of formula (I). Formula (I) is defined in a generic sense as three amino acids, where two in any order are cationic in nature and the third is one with a lipophilic side chain of 14-27 non-hydrogen atoms, where the tripeptide is also attached to a N atom optionally substituted by a branched or unbranched C1-C10 alkyl or aryl group that may incorporate up to two N, O, or S atoms, a group RaRb, RaRbRb or RbRbRa where Ra is C, O, S, or N and where Rb is C, and where both Ra and Rb may be substituted with C1-C4 alkyl groups, and a final group comprising 1-3 cyclic groups each of 5 or 6 non-hydrogen atoms with two or more of the cyclic groups optionally fused and one may optionally be substituted and be up to 15 non-hydrogen atoms. The compound as claimed offers a broad number of possible species given the variable positions throughout.
State of the Prior Art
The prior art recognizes the potential usage of LTX-109 in treatment of certain bacterial infections through disruption of the bacterial cell membrane. See e.g. Nilsson et al. Antimicrobial Agents and Chemotherapy 59:145-151, published 2015. Nilsson does not disclose any usage in treatment of enveloped viral infections.
Intervening art suggests that peptides might be developed to disrupt viral envelopes. See e.g. Jackman J Biochimica et Biophysica Acta – Biomembranes 1864:183821, published 19 November 2021. However, there is no suggestion from Jackman or other prior art references to prepare LTX-109, LTX-7, or LTX-12 and utilize them as antiviral peptides for treating enveloped viral infections.
LTX-109 and variants have been suggested as useful as antifungals against Saccharomyce cerevisiase and Zygosaccharomyces bailii, but that art does not suggest usage as a therapeutic against enveloped viruses. See e.g. Larsen et al. FEMS Yeast Research 15:fov011, published 2015.
Enveloped viruses encompass a wide number of families: Herpesviridae, Poxviridae, Hepadnaviridae, Retroviridae, Flaviviridae, Paramyxoviridae, Orthomyxoviridae, Filoviridae, Arenaviridae, Togaviridae, Coronaviridae, Bunyaviridae, and Rhbdoviridae (see e.g. Wisskirchen et al. Trends Pharmacol. Sci. 35:470-478, published 2014). As indicated in Table 1, the viruses differ in their genome organization and targets of any directly acting antiviral agents. A variety of antivirals are discussed but no “silver bullet” type antiviral that would target any and all enveloped viruses (see e.g. Table 2). Antibodies targeting viral envelope proteins are discussed, but this differs from targeting of the envelope itself.
Relative Skill of those in the Art
The relative skill of those in the art is high.
Predictability or Unpredictability of the Art
There is a general lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970).
It is not possible to predict a priori whether a given compound will act as a “silver bullet” against all enveloped viruses.
Amount of Direction or Guidance Given
The specification discloses that tripeptides with C-terminal modifications exhibit antiviral activity towards enveloped viruses, noting that they are cationic and bulky, and noting LTX-109 as one such compound (see e.g. p.1-2). The specification notes that antiviral activity of these compounds has not been previously recognized (see e.g. p.2). Four compounds are disclosed: LTX-109, Arg-Phe(4-(1-Naphthyl))-Arg-NH-CH2-CH2-Ph, LTX-7, and LTX-12 (see e.g. p.4-6). Assessment of the antiviral activity is described through use of TCID50 assays as well as microscopy (see e.g. p.9). The compounds may exert a direct membrane-affecting mechanism (see e.g. p.9).
Presence/Absence of Working Examples
Example 1 shows that a 1% LTX-109 solution disrupts lentivirus-like particles when viewed through electron microscopy. Example 2 shows that 1% LTX-109 serves to reduce infection of influenza A virus infection in vitro. Example 3 shows that 1% LTX-109 serves to reduce infection of respiratory syncytial virus infection in vitro. Example 4 shows that 1% LTX-109 serves to reduce infection of SARS-CoV-2 infection in vitro. Example 5 shows that 1% LTX-12 serves to reduce infection of SARS-CoV-2 infection in vitro and does not exhibit cytotoxicity. Example 6 shows that 1% LTX-7 serves to reduce influenza virus A infection in vitro and does not exhibit cytotoxicity.
Quantity of Experimentation Necessary
The claims reflect a variety of tripeptide derivatives that target an entire class of infections. The art does not recognize the claimed tripeptide derivatives as useful for antiviral purposes as admitted by the Applicants. The art additionally shows that antivirals take a variety of forms and target different aspects of specific viral families rather than being a “silver bullet”. There is low predictability in the art. The disclosure and examples show limited actual compounds and limited viral testing.
As a result, the skilled artisan is left with both a broad genus of compounds as well as a broad genus of conditions to treat. In this case, limited guidance on specific compounds is provided, and only three compounds are tested against highly limited examples of enveloped viruses. The onus is placed on them to prepare compounds covering the breadth of formula (I) as well as test them across a sufficient range of enveloped viruses to ensure that they act as a family to treat enveloped viral infections. While the in vitro results suggest that LTX-109, LTX-7, and LTX-12 might be useful for certain infections, they do not actually demonstrate that they are effective in treatment of actual subjects. The skilled artisan must also establish model systems in vivo for the claimed compounds and determine if the in vitro results based on electron microscopy and TCID50 assays extend to treatment in a subject. The resulting level of experimentation is beyond routine as the skilled artisan must examine the genus of both compounds of formula (I) and enveloped viral infections. The collective effort required to make and use the invention poses and undue burden on the part of the skilled artisan given the above factors.
In view of the Wands factors as discussed above, it is the Examiner’s opinion that the claims are not fully enabled and one of skill in the art would have to engage in undue experimentation to practice the invention as claimed herein, without a reasonable assurance of success.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY J MIKNIS whose telephone number is (571)272-7008. The examiner can normally be reached M-F 9-5.
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/ZACHARY J MIKNIS/Patent Examiner, Art Unit 1658