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 .
DETAILED ACTION
The amendment after non-final office action filed July 22, 2026 is acknowledged. Claims 2-8, 11-14, 23, 28-29, 31-35, 37-39 were cancelled, claims 1, 9-10, 19-21, 27, 30 were amended and claims 1-2, 9-10, 15-22, 24-27, 30, 36 are pending.
Election/Restrictions
The restriction was deemed proper and made final in the previous office action. Claims 1-2, 9-10, 15-22, 24-27, 30, 36 are examined on the merits of this office action.
Withdrawn Objections/Rejections
The objections to claims 1, 19-21, 30 are withdrawn in view of amendment of the claims filed July 22, 2026.
The rejection of claim 27 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claims filed July 22, 2026.
The rejection of claims 1-2, 15- 22, 24-27, 30, 36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Piu (WO2019140012, cited in Applicants IDS) is withdrawn in view of amendment of the claims filed July 22, 2026.
Maintained/Revised Rejection
Claim Rejections - 35 USC § 103
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.
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 1-2, 9-10, 15- 22, 24-27, 30, 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Piu (WO2019140012, cited in Applicants IDS).
*Applicants have amended claim 1 to narrow the range of BDNF to be administered, and thus, the rejection has been amended accordingly to reflect this. Furthermore, claim 10 was amended to recite “up to 0.4 mg of BDNF”. Given that claim 1, claim from which claim 10 depends on, claims about 0.3 mg to about 1.90 mg”, the range from claim 9 can only be about 0.3 mg up to 0.40 mg.
Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Regarding claim 1, Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range of claims 1, 9-10. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
Response to Applicant’s Arguments
Applicant argues that “Solely to expedite the prosecution of the present application, without prejudice or disclaimer, claim 1 has been amended.
As discussed above, Piu fails to teach "wherein the otic composition comprises from about 0.3 mg to about 1.90 mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle."
Piu provides no teaching, suggestion, or reasonable expectation that administration of approximately from about 0.3 mg to about 1.90 mg of BDNF would provide the therapeutic efficacy demonstrated in the present application.
The Office Action asserts that the amount of BDNF is for treatment of in an otic formulations is a result effective variable. It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation." Applicant respectfully disagrees. Here, the Office Action has not identified any teaching in Piu or provided a sufficient articulation in view of Piu that administration of about 0.30 mg to about 1.90 mg of BDNF, or any dose within the presently claimed range, was recognized as producing the claimed therapeutic effect or represented an optimum therapeutic dose. Instead, the rejection simply relies on a general assertion that dose optimization would have been routine. Such a conclusory statement is insufficient to establish a prima facie case of obviousness.
Moreover, the Office has not provided a sufficient articulated reasoning with a rational underpinning to support its conclusion of obviousness. Rather, the rejection merely states that the claimed dose could have been optimized through routine experimentation without identifying any teaching or suggestion in the prior art that would have led a person of ordinary skill in the art to select the presently claimed dose range with a reasonable expectation of success. Such a conclusory assertion is insufficient to establish a prima facie case of obviousness.
The present application further provides objective evidence of the criticality of about 0.3 mg of BDNF as unexpected results. Specifically, the application provides that administration of approximately 0.30 mg of BDNF produces an unexpected and clinically critical therapeutic effect that is absent in the placebo group. For example, as shown in Figures 10-12 and discussed in paras. [00300]-[00302], approximately 67% of treated subjects achieved clinically meaningful improvement at both Day 57 and Day 85 on at least one speech-in-noise endpoint, whereas 0% of placebo subjects achieved comparable improvement at any timepoint. Furthermore, up to 44% of treated subjects demonstrated clinically meaningful improvement on sentence-based AEMT testing, while no placebo-treated subject met the corresponding endpoint. Importantly, the observed improvement corresponds to functionally meaningful changes in speech intelligibility of approximately -2 to -3 dB SNR, demonstrating unexpectedness of a clinically critical therapeutic outcome.
Nothing in Piu suggests that administration of approximately 0.30 mg of BDNF or more, or the presently claimed dose range, would have produced these clinically meaningful improvements with a reasonable expectation of success. Piu provides no teaching that would have led a person of ordinary skill in the art to expect that selection of the claimed dose would result in the magnitude and consistency of therapeutic efficacy demonstrated in the present application. Accordingly, the claimed invention exhibits unexpectedly critical results that strongly support the nonobviousness of the presently claimed dose range.
Accordingly, the Office has not established that one of ordinary skill in the art would have been motivated to select the presently claimed dose range with a reasonable expectation of achieving the demonstrated therapeutic effect. The rejection under 35 U.S.C. § 103 should therefore be withdrawn.
Applicants arguments have been fully considered but not found persuasive. The Examiner would like to point out that Piu does teach concentrations and injection volumes that overlap with the instant claims. Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05). Regarding Applicants arguments that the the amount is not regarded as a result effective variable, the Examiner respectfully disagrees. Piu specifically teaches “Clinical doses range from about 0.01% to about 0.25% (e.g., about 0.1 mg/ml to about 2.5 mg/ml) of growth factor (e.g., BDNF). In some cases, preparing such clinical doses (e.g., for use in a Phase 1 or Phase 2 clinincal trial) may require a 10X growth factor concentrate of 1 mg/ml to 25 mg/ml” (see paragraph 00649). Clearly the dosing result effective. Furthermore, MPEP716.02(d) states “To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960)”. In the instant case advocates have not established criticality inside and outside of the claimed range in figures 10 through 12 but rather one dosage. Nevertheless,
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range) (see MPEP 2144.05).
Furthermore, MPEP 2145 states “Evidence pertaining to secondary considerations must be taken into account whenever it has been properly presented; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007) ("the record establish[ed] such a strong case of obviousness" that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion); Leapfrog Enterprises Inc. v. Fisher-Price Inc., 485 F.3d 1157, 1162, 82 USPQ2d 1687, 1692 (Fed. Cir. 2007) ("given the strength of the prima facie obviousness showing, the evidence on secondary considerations was inadequate to overcome a final conclusion" of obviousness); and Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988). Office personnel should not evaluate rebuttal evidence for its "knockdown" value against the prima facie case, Piasecki, 745 F.2d at 1473, 223 USPQ at 788, or summarily dismiss it as not compelling or insufficient. Office personnel should weigh all relevant evidence of record in order to determine whether the claims would have been obvious based on a preponderance (more likely than not) standard, and then explain their conclusions.”
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, 9-10, 15- 22, 24-27, 30, 36 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-40 of AN18/603065 in view of Piu (WO2019140012, cited in Applicants IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating hearing loss or hearing impairment in a human subject, comprising intratympanically administering an otic composition to the human subject, wherein the otic composition comprises from about 0.3 mg to about 1.90mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of BDNF into the inner ear” (claim 1). The instant application further claims 0.30mg up to 0.40mg BDNF (claim 9); poloxamer 407 (claim 19); 14-18% wt% poloxamer 407 (Claims 19-21); free of non-aqueous solvents (claim 27); release over 5 days (claim 30); hearing loss from cochlear synaptopathy (Claim 36).
Co-pending AN18/603065 claims “A thermoreversible intratympanic composition comprising:a neurotrophic factor or pharmaceutically acceptable salt thereof, and from about 14% to about 25% by weight of Poloxamer 407, wherein the growth factor is BDNF or neurotrophin-3, wherein the composition does not comprise any additional growth factor other than BDNF or neurotrophin-3, and wherein the pharmaceutical composition provides sustained release of therapeutically effective amount of the growth factor into the ear following a single administration” (claim 21). Co-pending AN18/603065 claims wherein the pharmaceutical composition has a pH of from 7.0 to 8.0 (claim 23); wherein the pharmaceutical composition has an osmolarity of from 250 mOsm/L to 320 mOsm/L (claim 25); wherein the pharmaceutical composition comprises from 14% to 20% by weight of the poloxamer (Claim 27); wherein the pharmaceutical composition is formulated to provide sustained release of the growth factor into an inner ear for a period of at least 5 days following a single administration (Claim 30); wherein the pharmaceutical composition comprises between about 0.1 mg/ml to about 5 mg/ml of the growth factor (claim 35); the formulation of Co-pending AN18/603065 intended use is for hearing loss (see paragraph 0043-0045) but does not claim it. Co-pending AN18/603065 is silent to Poloxamer 407 (with the amounts) and the specific amounts of BDNF.
Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
It would have been obvious to one of ordinary skill in the art to modify co pending Application No. 18/603065 in view of Piu to employ the claimed method of treating hearing loss with the recited formulation parameters because Piu teaches that intratympanic sustained release BDNF formulations using parameters such as poloxamer 407 content, gel vehicle properties, pH, osmolality, viscosity, and gelation behavior enhance retention in the ear and prolonged delivery to the inner ear, thereby improving treatment of hearing loss. A skilled artisan would have been motivated to incorporate Piu’s taught parameters into the composition of Application No. 18/603065 with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicant argues that “Solely to expedite the prosecution of the present application, without prejudice or disclaimer, claim 1 has been amended to specify "wherein the otic composition comprises from about 0.3 mg to about 1.90 mg of brain-derived neurotrophic factor (BDNF) and an auris- acceptable vehicle," which is not taught or suggested in Piu. Nor is such dosing range disclosed in any of the reference claims cited as the basis of the aforementioned double patenting rejections. Reconsideration and withdrawn of the double patenting rejections raised in the Office Action are respectfully requested.
Applicants arguments have been fully considered but not found persuasive. The Examiner would like to point out that Piu does teach concentrations and injection volumes that overlap with the instant claims. Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05). Regarding Applicants arguments that the the amount is not regarded as a result effective variable, the Examiner respectfully disagrees. Piu specifically teaches “Clinical doses range from about 0.01% to about 0.25% (e.g., about 0.1 mg/ml to about 2.5 mg/ml) of growth factor (e.g., BDNF). In some cases, preparing such clinical doses (e.g., for use in a Phase 1 or Phase 2 clinincal trial) may require a 10X growth factor concentrate of 1 mg/ml to 25 mg/ml” (see paragraph 00649). Clearly the dosing result effective. Furthermore, MPEP716.02(d) states “To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960)”. In the instant case advocates have not established criticality inside and outside of the claimed range in figures 10 through 12 but rather one dosage.
Claims 1-2, 9-10, 15- 22, 24-27, 30, 36 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 9-10, 14-15, 21-22, 26, 28-40 of AN16/873803 in view of Piu (WO2019140012, cited in Applicants IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating hearing loss or hearing impairment in a human subject, comprising intratympanically administering an otic composition to the human subject, wherein the otic composition comprises from about 0.3 mg to about 1.90mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of BDNF into the inner ear” (claim 1). The instant application further claims 0.30mg up to 0.40mg BDNF (claim 9); poloxamer 407 (claim 19); 14-18% wt% poloxamer 407 (Claims 19-21); free of non-aqueous solvents (claim 27); release over 5 days (claim 30); hearing loss from cochlear synaptopathy (Claim 36).
Co-pending AN16/873803 claims “An otic formulation comprising about 0.005% to about 0.5% by weight of a growth factor and an auris-acceptable vehicle being a thermoreversible gel comprising poloxamer 407, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear, wherein the growth factor is brain-derived neurotrophic factor (BDNF)” (Claim 1). Co-pending AN16/873803 further claims gelation viscosity 15000-3000000 cP (Claim 6); 100-1000mOsm/L (claim 1); 19-42 degrees Celsius (claim 9); pH 7-8 (claim 10); 15-17 wt% poloxamer 407 (claim 1); treatment of hearing loss (claim 38). Co-pending AN16/873803 is silent to the specific amounts of BDNF. Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicants reiterate the aforementioned arguments with respect to the instant rejection. The Office’s rebuttal of these arguments remains the same and is incorporated herein by reference.
Claims 1-2, 9-10, 15-22, 24-27, 30, 36 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-8, 11-15, 20-23 of AN17/794935 in view of Piu (WO2019140012, cited in Applicants IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating hearing loss or hearing impairment in a human subject, comprising intratympanically administering an otic composition to the human subject, wherein the otic composition comprises from about 0.3 mg to about 1.90mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of BDNF into the inner ear” (claim 1). The instant application further claims 0.30mg up to 0.40mg BDNF (claim 9); poloxamer 407 (claim 19); 14-18% wt% poloxamer 407 (Claims 19-21); free of non-aqueous solvents (claim 27); release over 5 days (claim 30); hearing loss from cochlear synaptopathy (Claim 36).
Co-pending AN17/794935 claims A method of treating an otic disease comprising administering an otic formulation comprising 0.005% to 0.5% by weight of brain-derived neurotrophic factor (BDNF) and poloxamer 407” (see claim 1). Co-pending AN17/794935 claims wherein the otic formulation comprises from about 15 wt% to about 17 wt%of the poloxamer 407 (claim 6); intratympanic injection (claim 13); treating hearing loss (claim 15); osmolarity from about 100 mOsm/L to about 1000 mOsm/L; pH from about 7.0 to about 8.0 (claims 7-8). Co-pending AN17/794935 is silent to specific amounts of BDNF.
Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range of claims 1, 9-10. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicants reiterate the aforementioned arguments with respect to the instant rejection. The Office’s rebuttal of these arguments remains the same and is incorporated herein by reference.
Claims 1-2, 9-10, 15- 22, 24-27, 30, 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10751281 in view of Piu (WO2019140012, cited in Applicants IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating hearing loss or hearing impairment in a human subject, comprising intratympanically administering an otic composition to the human subject, wherein the otic composition comprises from about 0.3 mg to about 1.90mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of BDNF into the inner ear” (claim 1). The instant application further claims 0.30mg up to 0.40mg BDNF (claim 9); poloxamer 407 (claim 19); 14-18% wt% poloxamer 407 (Claims 19-21); free of non-aqueous solvents (claim 27); release over 5 days (claim 30); hearing loss from cochlear synaptopathy (Claim 36).
US Patent No. ‘281 “A method of treating or alleviating hearing loss, the method comprising intratympanically administering an otic composition to a subject in need thereof, wherein the otic composition comprises an otic hair cell growth factor and an auris acceptable gel, wherein the otic hair cell growth factor is multiparticulate and non-microencapsulated, and wherein the otic hair cell growth factor is not a glial cell-line derived neurotrophic factor (GDNF)” (claim 1). US Patent No. ‘281 further claims herein the auris acceptable gel has a gelation viscosity between about 100 cP and about 1,000,000 cP (claim 2); herein the otic composition has an osmolarity of from about 100 mOsm/L to about 500 mOsm/L (claim 4); wherein the otic composition has a pH between 7.0 and 8.0 (claim 6); wherein the otic hair cell growth factor is BDNF(claim 8); the auris acceptable gel is a thermoreversible gel (Claim 14); herein the thermoreversible gel comprises a copolymer of polyoxyethylene and polyoxypropylene (Claim 15). US Patent No. ‘281 is silent to Poloxamer 407 and amounts thereof and the specific amounts of BDNF.
Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range of claims 1, 9-10. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
It would have been obvious to one of ordinary skill in the art to modify US Patent No. ‘281 in view of Piu to employ the claimed method of treating hearing loss with the recited formulation parameters because Piu teaches that intratympanic sustained release BDNF formulations using parameters such as poloxamer 407 content, gel vehicle properties, pH, osmolality, viscosity, and gelation behavior enhance retention in the ear and prolonged delivery to the inner ear, thereby improving treatment of hearing loss. A skilled artisan would have been motivated to incorporate Piu’s taught parameters into the composition of US Patent NO. ‘281 with a reasonable expectation of success.
Response to Applicant’s Arguments
Applicants reiterate the aforementioned arguments with respect to the instant rejection. The Office’s rebuttal of these arguments remains the same and is incorporated herein by reference.
Claims 1-2, 9-10, 15- 22, 24-27, 30, 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11123285 in view of Piu (WO2019140012, cited in Applicants IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating hearing loss or hearing impairment in a human subject, comprising intratympanically administering an otic composition to the human subject, wherein the otic composition comprises from about 0.3 mg to about 1.90mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of BDNF into the inner ear” (claim 1). The instant application further claims 0.30mg up to 0.40mg BDNF (claim 9); poloxamer 407 (claim 19); 14-18% wt% poloxamer 407 (Claims 19-21); free of non-aqueous solvents (claim 27); release over 5 days (claim 30); hearing loss from cochlear synaptopathy (Claim 36).
US Patent No. ‘285 claims “A pharmaceutical composition comprising: between about 0.1 mg/ml to about 20 mg/ml of one and no more than one growth factor selected from brain-derived neurotrophic factor (BDNF) or neurotrophin-3, or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a thermoreversible gel formulated for intratympanic administration, wherein the pharmaceutical composition comprises from 14% to 17% by weight of Poloxamer 407, and wherein the growth factor is not a glial cell-line derived neurotrophic factor (GDNF)” (Claim 1). US Patent No. ‘285 claims wherein the pharmaceutical composition has a pH of from 7.0 to 8.0 (claim 2); wherein the pharmaceutical composition has an osmolarity of from 250 mOsm/L to 320 mOsm/L (claim 4); wherein the pharmaceutical composition comprises from 15% to 16% by weight of Poloxamer 407 (claim 5); formulated to provide sustained release of the growth factor into an inner ear for a period of at least 5 days following a single administration (Claim 7); wherein the pharmaceutical composition comprises between about 0.1 mg/ml to about 5 mg/ml of the growth factor (claim 13).
US Patent No. ‘285 is silent to specific amounts of BDNF.
Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range of claims 1, 9-10. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
Response to Applicant’s Arguments
Applicants reiterate the aforementioned arguments with respect to the instant rejection. The Office’s rebuttal of these arguments remains the same and is incorporated herein by reference.
Claims 1-2, 9-10, 15- 22, 24-27, 30, 36 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No.11969501 in view of Piu (WO2019140012, cited in Applicants IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating hearing loss or hearing impairment in a human subject, comprising intratympanically administering an otic composition to the human subject, wherein the otic composition comprises from about 0.3 mg to about 1.90mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of BDNF into the inner ear” (claim 1). The instant application further claims 0.30mg up to 0.40mg BDNF (claim 9); poloxamer 407 (claim 19); 14-18% wt% poloxamer 407 (Claims 19-21); free of non-aqueous solvents (claim 27); release over 5 days (claim 30); hearing loss from cochlear synaptopathy (Claim 36).
US Patent No. ‘501 claims “ A pharmaceutical composition comprising: one and no more than one growth factor selected from brain-derived neurotrophic factor (BDNF) or neurotrophin-3, or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a thermoreversible gel formulated for intratympanic administration, wherein the pharmaceutical composition comprises from 14% to 17% by weight of Poloxamer 407, and wherein the pharmaceutical composition provides sustained release of therapeutically effective amount of the growth factor into the ear following a single administration” (claim 1). US Patent No. ‘501 further claims wherein the pharmaceutical composition has a pH of from 7.0 to 8.0 (Claim 3); wherein the pharmaceutical composition has an osmolarity of from 250 mOsm/L to 320 mOsm/L (claim 5); wherein the pharmaceutical composition comprises from 14% to 16% by weight of the poloxamer (claim 7); wherein the pharmaceutical composition is formulated to provide sustained release of the growth factor into an inner ear for a period of at least 3 days following a single administration (claim 9); wherein the pharmaceutical composition is formulated to provide sustained release of the growth factor into an inner ear for a period of at least 5 days following a single administration (Claim 10); wherein the pharmaceutical composition comprises between about 0.1 mg/ml to about 5 mg/ml of the growth factor (claim 15).
US Patent No. ‘501 is silent to specific amounts of BDNF.
Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range of claims 1, 9-10. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
Response to Applicant’s Arguments
Applicants reiterate the aforementioned arguments with respect to the instant rejection. The Office’s rebuttal of these arguments remains the same and is incorporated herein by reference.
Claims 1-2, 9-10, 15- 22, 24-27, 30, 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No.9744126 in view of Piu (WO2019140012, cited in Applicants IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating hearing loss or hearing impairment in a human subject, comprising intratympanically administering an otic composition to the human subject, wherein the otic composition comprises from about 0.3 mg to about 1.90mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of BDNF into the inner ear” (claim 1). The instant application further claims 0.30mg up to 0.40mg BDNF (claim 9); poloxamer 407 (claim 19); 14-18% wt% poloxamer 407 (Claims 19-21); free of non-aqueous solvents (claim 27); release over 5 days (claim 30); hearing loss from cochlear synaptopathy (Claim 36).
US Patent No. ‘126 claims “ An intratympanic composition for use in the treatment of an otic disorder, the composition comprising: from 4.5 wt % to 6 wt % multiparticulate dexamethasone in the form of micronized and non-coated particles; from 14 wt % to 16 wt % poloxamer; and water, wherein the composition has a pH of 7.0-7.8, an osmolarity of 270-320 mOsm/L, and a gelation temperature of 20-30° C (claim 14). US Patent No. ‘126 further claims wherein the poloxamer is poloxamer 407 (claim 16) and wherein the otic disorder is selected from Meniere's disease, Autoimmune ear disease (AIED), otitis media, acoustic trauma induced sensorineural hearing loss, drug induced sensorineural hearing loss, sensorineural hearing loss due to infection, idiopathic sensorineural hearing loss, vertigo, tinnitus, and combinations thereof (Claim 9). US Patent No. ‘126 is silent to specific amounts of BDNF.
Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range of claims 1, 9-10. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
Response to Applicant’s Arguments
Applicants reiterate the aforementioned arguments with respect to the instant rejection. The Office’s rebuttal of these arguments remains the same and is incorporated herein by reference.
Claims 1-2, 9-10, 15- 22, 24-27, 30, 36 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No.10272034 in view of Piu (WO2019140012, cited in Applicants IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating hearing loss or hearing impairment in a human subject, comprising intratympanically administering an otic composition to the human subject, wherein the otic composition comprises from about 0.3 mg to about 1.90mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of BDNF into the inner ear” (claim 1). The instant application further claims 0.30mg up to 0.40mg BDNF (claim 9); poloxamer 407 (claim 19); 14-18% wt% poloxamer 407 (Claims 19-21); free of non-aqueous solvents (claim 27); release over 5 days (claim 30); hearing loss from cochlear synaptopathy (Claim 36).
US Patent No. ‘034 claims “ A method of providing sustained release of an auris sensory cell modulator into an ear of a patient, the method comprising intratympanically administering an otic composition to said patient, wherein the otic composition comprises a multiparticulate and non-microencapsulated auris sensory cell modulator and an auris acceptable gel, wherein the auris sensory cell modulator is an otic hair cell growth factor modulator, wherein the otic hair cell growth factor modulator is not a growth factor, and wherein the otic hair cell growth factor modulator modulates a receptor of at least one otic hair cell growth factor” see claim 1. US Patent No. ‘034 claims wherein the auris acceptable gel has a gelation viscosity between about 100 cP and about 1,000,000 cP (Claim 2); wherein the otic composition has an osmolarity of about 100 mOsm/L to about 500 mOsm/L (Claim 4); wherein the otic composition has a pH between 7.0 and 8.0 (Claim 6); BDNF (claim 7).
US Patent No. ‘034 is silent to Poloxamer 407 and amounts thereof and the specific amounts of BDNF.
Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range of claims 1, 9-10. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
It would have been obvious to one of ordinary skill in the art to modify US Patent No. ‘034 in view of Piu to employ the claimed method of treating hearing loss with the recited formulation parameters because Piu teaches that intratympanic sustained release BDNF formulations using parameters such as poloxamer 407 content, gel vehicle properties, pH, osmolality, viscosity, and gelation behavior enhance retention in the ear and prolonged delivery to the inner ear, thereby improving treatment of hearing loss. A skilled artisan would have been motivated to incorporate Piu’s taught parameters into the composition of US Patent NO. ‘034 with a reasonable expectation of success.
Response to Applicant’s Arguments
Applicants reiterate the aforementioned arguments with respect to the instant rejection. The Office’s rebuttal of these arguments remains the same and is incorporated herein by reference.
Claims 1-2, 9-10, 15- 22, 24-27, 30, 36 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No.11918653 in view of Piu (WO2019140012, cited in Applicants IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating hearing loss or hearing impairment in a human subject, comprising intratympanically administering an otic composition to the human subject, wherein the otic composition comprises from about 0.3 mg to about 1.90mg of brain-derived neurotrophic factor (BDNF) and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of BDNF into the inner ear” (claim 1). The instant application further claims 0.30mg up to 0.40mg BDNF (claim 9); poloxamer 407 (claim 19); 14-18% wt% poloxamer 407 (Claims 19-21); free of non-aqueous solvents (claim 27); release over 5 days (claim 30); hearing loss from cochlear synaptopathy (Claim 36).
US Patent No. ‘653 claims “ An otic pharmaceutical formulation comprising:
a) a therapeutic agent, or pharmaceutically acceptable prodrug or salt thereof, and
b) triglycerides comprising long-chain fatty acids;
wherein the triglycerides are present in an amount that is sufficient to stabilize the therapeutic agent for injection into an ear, and wherein the otic pharmaceutical formulation is free of waxes and comprises at least about 50% by weight of the triglycerides” (see claim 1). US Patent No. ‘653 claims comprising BDNF (claim 13), poloxamer (claim 7); wherein the otic pharmaceutical formulation has a viscosity between about 10 cP to about 10,000 cP (Claim 9); for use in the treatment of an otic disease or condition associated with the outer, middle, and/or inner ear (Claim 19).
US Patent No. ‘653 is silent to Poloxamer 407 and amounts thereof and the specific amounts of BDNF and treating hearing loss.
Piu teaches a method of treating hearing loss comprising administering an otic formulation comprising a therapeutically effective amount of a growth factor and an auris-acceptable vehicle, wherein the otic formulation is formulated to provide sustained release of the growth factor into the inner ear to promote formation of synapses (see abstract, claim 1, paragraph 0044). Piu teaches wherein the growth factor is BDNF (see claims 2-3). Piu teaches intratympanic delivery to the inner ear (see Figure 10, paragraph 0031) and sustained delivery of the BDNF (see paragraph 0024, Figure 3A). Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643).
Piu teaches administering 0.2 mL of the growth factor formulation (BDNF formulation). The injection of 0.2 mL of 1.5 mg/mL formulation would result in an amount within the claimed range of claims 1, 9-10. Piu teaches additionally teaches a range of 0.05-.5% BDNF (see paragraph 00652 Regarding claim 2, Piu teaches recombinant BDNF (see paragraphs 00652, 00585). Regarding claims 15-16, Piu teaches wherein the vehicle is an auris-acceptable gel (see claims 4-5). Regarding claim 17, Piu teaches “wherein the auris-acceptable gel comprises a copolymer of polyoxyethylene and polyoxypropylene” (Claim 11). Regarding claim 18, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12). Regarding claims 19-21, Piu teaches wherein the copolymer is poloxamer 407 (see claim 12) and 16% poloxamer 407 which falls within the amounts of instant claims 19-21. Regarding claim 22, Piu teaches “wherein the auris-acceptable gel has a gelation viscosity from about 15,000 cP and about 3,000,000 cP”. Regarding claim 24, Piu teaches “wherein the otic formulation has an osmolality from about 100 mOsm/L to about 1000 mOsm/L.” Regarding claim 25, Piu teaches “wherein the otic formulation has a gelation temperature from about 19°C to about 42°C” (claim 9). Regarding claim 26, Piu teaches “wherein the otic formulation has a pH from about 7.0 to about 8.0” (claim 10). Regarding claim 27, Piu teaches wherein the formulations are aqueous and wherein commonly used solvents (including non-aqueous solvents) are eliminated (see paragraph 00410, see paragraph 00273, 00269, 00275, see also paragraph 0484). Regarding claim 30, Piu teaches wherein the formulation releases the therapeutic agent, i.e. BDNF, for over a period of 5 days (see paragraph 00537, 00703). Nevertheless, the limitation of “provides sustained release of BDNF into the inner ear over a period of at least 5 days” is result oriented effect that is inherent to the properties of the otic formulation of Piu. Piu teaches the same method, same extended release formulation and amounts thereof and thus, these effects will necessarily occur. Regarding claim 36, Piu teaches treatment and repair of cochlear synaptopathy (see paragraph 00645).
Piu teaches wherein the formulation is 1.5 mg/mL (0.15%)(see paragraph 0026, Figure 5A, B and C) and also 0.05 mg/mL BDNF in P407 (see paragraph 00643). Piu additionally teaches administering 0.2 mL of the 0.15% BDNF formulation, and thus would meet the limitations of 0.3 mg of BDNF (see paragraph 00651). Piu additionally teaches 1.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL up to 25 mg/mL (see paragraphs 00648-00649). Piu doesn’t specifically teach .2, .3 or .4 mg of BDNF (as recited in instant claims 9-10) even the volumes and concentration overlap. However, the amount of BDNF is for treatment of in an otic formulations is a result effective variable (see paragraph 00649). It would have been obvious to a person of ordinary skill in the art to optimize the concentration based on the teachings of the prior art through routine experimentation to achieve a desired therapeutic amount, including the claimed doses, with a reasonable expectation of success (see MPEP 2144.05).
It would have been obvious to one of ordinary skill in the art to modify US Patent No. ‘653 in view of Piu to employ the claimed method of treating hearing loss with the recited formulation parameters because Piu teaches that intratympanic sustained release BDNF formulations using parameters such as poloxamer 407 content, gel vehicle properties, pH, osmolality, viscosity, and gelation behavior enhance retention in the ear and prolonged delivery to the inner ear, thereby improving treatment of hearing loss. A skilled artisan would have been motivated to incorporate Piu’s taught parameters into the composition of US Patent NO. ‘653 with a reasonable expectation of success.
Response to Applicant’s Arguments
Applicants reiterate the aforementioned arguments with respect to the instant rejection. The Office’s rebuttal of these arguments remains the same and is incorporated herein by reference.
New Objections
It is suggested that claim 9 be amended as follows: “The method of claim 1, wherein the composition comprises about 0.3 mg up to 0.40 mg of BDNF” to clearly present the amount of BDNF that is encompassed by the claim given the dependency on claim 1.
Conclusion
No claims are allowed.
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 ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Primary Examiner, Art Unit 1654
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