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 .
Maintained rejections
Rejection under 35 USC 112(a) is maintained. Applicants have amended the claims to limit the hearing loss to “hearing loss associated with sensory hair cell damage or loss”. This limitation is already addressed in the rejection of record. Additional reference to the specification (Example 1) made in the maintained rejection is in response to the amendment and is underlined.
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 sensory hair cell damage or loss and hearing loss is selected from the group consisting of 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 to 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. However, on page 79, line 14-15, the specification states “This analysis indicated that by itself, AG1478 had no impact on the proliferation and differentiation of endogenous SCs and HCs.” It appears that the Example demonstrates that EFGR inhibitor AG1478 was not successful in restoring SC or HC regeneration, which indicates that it is not predictable which EFGRs, if any are enabled for the claimed method.
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.
Example 4 indicates that the tested inhibitors protected against cisplatin induced hearing loss.
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.
Reply to applicant’s remarks
Applicants have traversed the above rejection. The first argument is directed to claims being supported in Example 4. Example 4 is directed to cisplatin induced hearing loss. Examiner has already acknowledged that protection of cisplatin induced hearing loss is enabled. Example 4 does not provide support for the full scope of the agents encompassed by the term “EFGR inhibitor” nor to the dozens of disorders encompassed by applicant’s definition of hearing loss.
Applicants also provide data presented by Vjjayakumar et al in 2024, which is a post-filing date publication. MPEP2164.05(a) states that the specification must be enabling as of the filing date:
“The state of the art existing at the filing date of the application is used to determine whether a particular disclosure is enabling as of the filing date. Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004) (Stating that “a patent document cannot enable technology that arises after the date of application.”). Information published for the first time after the filing date generally cannot be used to show what was known at the time of filing. In reGunn, 537 F.2d 1123, 1128, 190 USPQ 402,405-06 (CCPA 1976); In re Budnick, 537 F.2d 535, 538, 190 USPQ 422, 424 (CCPA 1976) (In general, if an applicant seeks to use a patent to prove the state of the art for the purpose of the enablement requirement, the patent must have an issue date earlier than the effective filing date of the application.). While a later dated publication cannot supplement an insufficient disclosure in a prior dated application to make it enabling, an applicant can offer the testimony of an expert based on the publication as evidence of the level of skill in the art at the time the application was filed. Gould v.Quigg, 822 F.2d 1074, 1077, 3 USPQ2d 1302, 1304 (Fed. Cir. 1987).”
The data obtained by Vijayakumar was obtained 7 years after the priority date of the current application. Additionally, Vijayakumar only suggests that reduction of noise induced hearing loss is enabled, not the full broad scope of the current claims and only with EFGR inhibitors (page 2, column 2, paragraph 3). Also, the evidence suggests that EFGR inhibitors only protect against noise induced hearing loss, not treat hearing loss.
Conclusion
Claims 1-19 are pending
Claims 1-19 are rejected
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YEVGENY VALENROD whose telephone number is (571)272-9049. The examiner can normally be reached Mon-Fri 9am-5pm.
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/YEVGENY VALENROD/Primary Examiner, Art Unit 1628
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