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 .
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 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for a method of treating hearing loss other than cisplatin-induced hearing loss. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Claims 1-6 and 15-19 are directed to a method of treating or prevention hearing loss.
Claims 7-14 are directed to a pharmaceutical composition and kit comprising an expression vector harboring a nucleic acid molecule encoding an active atonal-associated factor protein in combination with EGFR signaling inhibitor. Since the sole disclosed pharmaceutical utility of the claimed composition and kit is in treatment or prevention of hearing loss, enablement of the composition is evaluated based on that utility.
MPEP2164.01(c):
When a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation. See In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991) (claiming a chimeric gene capable of being expressed in any cyanobacterium and thus defining the claimed gene by its use).
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." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
Nature of the invention and Breadth of the claims:
The claims are directed to a method for treatment or prevention of hearing loss comprising administering to a subject in need thereof an inhibitor of EGFR signaling. Hearing loss is a generic term for a variety of conditions that result in reduced auditory capacity of a subject. Claim 1 limits hearing loss to hearing loss associated with tinnitus, ringing, Presbyacusis, auditory neuropathy, acoustic trauma, acoustic neuroma, Pendred syndrome, Usher syndrome, Wardenburg syndrome, non-syndromic sensorineural deafness, otitis media, otosclerosis, Meniere's disease, ototoxicity or labyrinthitis. However, many of the conditions listed are themselves generic and encompass various diseases and mechanism that contribute to hearing loss. For example, ototoxicity is hearing loss resulting from taking a medication. Ototoxicity can affect cochlea, vestibule semicircular canals and otoliths by different mechanisms depending on the therapeutic that is causing it. The nature of the claimed therapeutic agent to be administered is also very broad as illustrated by the various targets listed in claim 4 and types of inhibitory agents listed in claims 6.
State of the prior art and level of predictability in the art:
Whether any of the claimed EGFR signaling inhibitors are effective at treating any type of hearing loss is highly unpredictable.
Koutras et al (Acta Oncologica, 2008, 47(6), 1171-1173) reports irreversible ototoxicity associated with the use of erlotinib (an inhibitor of EGFR). On page 1172 Koutras et al report administrating erlotinib monotherapy to a patient. Approximately half an hour following administration of the first dose the patient reported sudden onset of aural fullness, tinnitus, dizziness and severe bilateral hearing loss. The symptoms subsequently partially subsided but re-appeared with greater intensity after each subsequent dose (page 1172. Column 1, 2nd paragraph). Koutras et al attribute the observed hearing loss to inhibition of EGFR and HER 2, 3 and 4 receptors (page 1172, column 2, 2nd paragraph). Even if one was to argue that the hearing loss observed was a result of some other mechanism unrelated to EGRF inhibition, evidence clearly indicates that EGFR inhibition did not prevent hearing loss.
A similar report by Lim et al (European Journal of Otolaryngology, 2022, 38(64) 1-4) reports ototoxicity after treatment with Osimertinib (EGFR inhibitor).
Liu et al (Neural Plasticity, Volume 2021, Article ID 5522717, 12 pages; published 2022) explores the role of MAPK and AKT signaling on loss of auditory sensory hair cells (HC). On page 3, column 1, paragraph 4, Liu teaches that different MARK kinases have different effects on HCs. On page 4, 2nd paragraph Liu teaches “IGF1 protects HCs from aminoglycosides by activating the IGF1 receptor and its two main downstream pathways, PI3K/Akt and MEK/ERK…” The teachings of Liu are in direct contradiction to the instantly claimed method. Liu teaches activation of PI3K AKT and ERK results in protection of HCs while instant claims are directed to inhibition PI3K AKT and ERK (see claim 4). In the “conclusion” section on pages 6-7 Liu teaches:
“Although their effects on cochlear HC proliferation and survival have been studied extensively, there are likely many levels of cross-communication between signaling cascades that are still undiscovered. Research in this field is becoming increasingly prevalent, as is research into the mechanisms of regulated development and survival of auditory HCs. A number of otoprotective drug therapies target different levels along these signaling pathways to promote auditory HC viability and hearing protection.” Here Liu teaches that the signal transduction pathway leading hearing loss is complex and there is cross communication between different pathways. Liu et al represent the current state of the art as it was published in 2022.
White et al (Developmental biology, 2012 363, 191-200; submitted with IDS) teaches that EGFR signaling is required for proliferation of auditory hair cells (Abstract; page 197, column 1, paragraphs 3-5). White also teaches that additional signaling pathways via PI3K may be operating separately from EGFR pathway (page 199, column 1, paragraph 3). The teachings of White suggest that EGFR signaling is required for hair cell proliferation. This teaching is in contrast to the claimed method of inhibiting EGFR signaling in treatment of hearing loss.
Amount of direction provided by the inventor and existence of working examples:
Example 1 implicates EGFR signaling in HC regeneration.
Example 2 is a prophetic example that will examine molecular pathways in HC regeneration
Example 3 is also a prophetic example examining therapeutic potential of EGFR inhibitors in Atoh1-overexapressing Mice.
Relative skill of those in the art and quantity of experimentation needed to make or use the invention:
Although a person of ordinary skill in the art would have an advanced degree in Medicine or biological science, it would not be possible to practice the claimed method in a predictable way without undertaking a significant amount of experimentation. As evidenced by the cited art, EGFR inhibitors have been documented in causing ototoxicity, which is the opposite of the claimed effect. It has also been documented that activation of PI3K, AKT, MEK and ERK pathways leads to protection of HCs which is also the opposite of the currently claimed method. Lastly, art teaches that signal transduction pathways involved leading to hearing loss are complex and include cross-communication between different pathways. Art acknowledges that this is an area of interest with regards to treatment of hearing loss but does not suggest that the instantly claimed method would result in treatment. The examples provided in the specification do not provide sufficient data to enable the claimed method. While Example 1 suggests EGFR inhibition might play a role in HC regeneration, Example 1 states: “This analysis indicated that by itself, AG1478 had no impact on the proliferation and differentiation of endogenous SCs and HCs after 7 days.” AG1478 is a potent EGFR inhibitor. Example 1 also finds that PLC inhibition by U73122 did not enhance conversion of rate of Atoh1-induced HCs. PLC is part of EGFR signaling. The results appear to confirm the teaching in the art that mechanisms involved in treatment of hearing loss are complex and more studies are needed.
Thus, given these considerations, one of ordinary skill in the art would not be able to practice the claimed method such that it can be used as contemplated in the specification without first engaging in substantial and undue experimentation. Therefore, the claims are rejected under 35 U.S.C. §112, first paragraph, as lacking and enabling disclosure.
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, 3-6, 15, 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,883,491. Although the claims at issue are not identical, they are not patentably distinct from each other. Claims 1-8 of the ‘491 patent are directed to: A method of treating cisplatin induced hearing loss comprising administering to the subject inhibitor of EGFR signaling (claim 1); in combination with one or more regenerative agents (claim 2); treating cisplatin-induced hair cell loss (claim 5). Cisplatin-induced hearing loss is within the scope of the current claims.
Conclusion
Claims 1-19 are pending
Claims 1-19 are rejected
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/YEVGENY VALENROD/Primary Examiner, Art Unit 1628