DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a combination of steps, components, and functions that were not clearly contemplated in combination in the original disclosure. While recitations of a polymer composition that is composed of a functional polymer at 5 to 15 wt%, a crosslinker at 0.05 to 0.6 wt%, and water with a gelation time of 45 seconds to 60 minutes at 20⁰C are detailed, the embodiments that also have a pH of about 5.5 to 6.0, a viscosity of 100 to about 1000 mPa•s, or a gelation time of about 2 minutes to about 8 minutes at a temperature of about 37° C are not structurally identified (see instant specification pages 4-5).
The identity and relative amounts of the functional groups on the polymer and trilysine, as well as overall concentration and the pH conditions under which they react, have impact on the rate at which gelation occurs. The functional polymer, as claimed, can have any number of any type of functional groups that are reactive with functional groups in the instantly claimed trilysine. The applicant cites Pathak et al. who notes the utility of amine-N-hydroxysuccinimide (NHS) chemistry as well as the need for more than two functional groups per polymer molecule in order for a gel to form (see US Patent 7,332,566 column 9 line 37-column 10 line 16, column 11 lines 33-60, column 20 line 56-column 21 line 2, column 22 line 18-column 23 line 59, tables 1-2). They note the amine-NHS chemistry as useful for in situ reactions on live tissue due to its gelation rate that occurs within 10 minutes. They also comment on the pH sensitivity of the reaction where a reaction pH range between 5 and 12 is preferred and elevated pH increases the rate of reaction. Their example employing tryline as a crosslinker with a functional polymer employs a tetra-NHS containing four armed polymer as the functional polymer. The polymer composition, at an unspecified pH between 4 and 9.5, provided trilysine at 0.9 wt% and the polymer at 19 wt% in water, where gelation occurred within 4 seconds which is outside the functional requirements of the instant composition (see examples 11-12 and figure 12 sample “tri-lysine”).
The instant specification provides a PEG-trilysine system with a polyethylene glycol functional polymer and trilysine at undisclosed concentrations in water (see example 1). As the pH of the reaction solution is lowered from 9.9 to 8.4 and the trilysine concentration is lowered, the gelatin time increases from 3 seconds to about 62 seconds at room temperature. Further lowering of the trilysine concentration and including dexamethasone at 2 to 12 wt% produced a gelation time of 55 seconds at pH 8.4 (see example 3). Here the instantly claimed components are present, but the instantly claimed proportions, pH, and gelation are not met, nor can they be extrapolated from the examples. Instant example 11 again combines undisclosed concentrations of a functional PEG polymer and trilysine, where a buffer with a desired pH is added to achieve a final composition pH that varied from 6.78 to 7.44 and attained gelation times that ranged from 11 to 3 minutes, respectively. Instant claim 1 recites the composition to have a pH of about 5.5 to about 6 and a gelatin time of about 2 to about 8 minutes. The example provides the closest teaching of a composition with the required functionality and even then, the function is only embraced by the approximate nature of the upper end of the recited pH range. Further, the exemplary composition does not include dexamethasone, the concentrations of trilysine and the generically described functional polymer, the identity of the functional polymer, or the claimed initial viscosity of the composition. In addition, the instant specification appears to distinguish room temperature, as was the environment in the example, from body temperature that is disclosed as including the “about 37⁰C” that is required by the instant claim. This is another instance of this closest example not fully meeting the requirements of the instant claims. Thus, it is not evident to what degree the example(s) illustrates the behavior of the required composition and reaction conditions.
There is no discussion provided by the disclosure aligning structural features of a composition in regard to the identity of the functional polymer that, when included in the composition with its required trilysine concentration, viscosity and pH, is able to meet the required gelation time constraints that are claimed. In the context of the more specifically recited functional polymer of instant claim 12, there is no disclosed connection between this variety of functional polymer and the currently claimed composition functionality. As a result, there is an inadequate structure-function correlation for the claimed method the artisan of ordinary skill would not have deemed the applicant to be in possession of the invention as currently claimed at the time of filing.
This is a new matter rejection
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “said extended release otic dexamethasone composition comprises…a cross-linking polymer composition having a pH of about 5.5 to about 6.0 and a gelation time of about 2 minutes to about 8 minutes at a temperature of about 37°C…wherein the extended release otic dexamethasone composition has an initial viscosity of about 100 mPa•s to about 1000 mPa•s prior to transitioning to the gel substance”.
It is unclear what physical feature/behavior constitutes gelation in the context of the invention as currently claimed. A variety of different possible, non-limiting, metrics of gelation are mentioned in the instant specification such as coating of a rotating magnetic stir bar and retention of a magnetic stir bar in a sample in the presence of an externally applied magnetic field (see example 14). Jarett et al. (previously cited) discuss gelation as when the composition applied to a surface shows substantially no flow when the surface is tilted at an angle of about 60 degrees which is also a broad definition (see paragraph 91). At the same time, the claims now recite that the composition has an initial viscosity “prior to transitioning to the gel substance” of about 100 to about 1000 mPa•s. Prior art describes injectable drug releasing compositions with this viscosity as gels (see Zanella et al. US PGPub No. 0246123 abstract and paragraphs 51 and 63). Thus, the behavior that is indicative of gelation is not clear such that its duration can be assessed to determine when a material is inside or outside the scope of those employed in the claimed methods.
Additionally, the viscosity of the composition can vary depending on how it is measured. For example, Jarrett et al. teach compositions composed of components and functions that embrace those instantly claimed (see abstract, paragraphs 25-26, 91, and 98). They also detail the inclusion of thixotropic components that provide little resistance to motion when under shear and forms a gel when static (see paragraph 57). Thus, the same material with a thixotropic polymer would exhibit a different viscosity depending on the amount of shear employed for the measurement. This creates situations where a single composition can be both inside and outside the scope of the claims, depending upon how it is assessed. As a result, the scope of compositions that qualify as the extended release otic dexamethasone composition which has an initial viscosity of about 100 mPa•s to about 1000 mPa•s prior to transitioning to the gel substance is unclear.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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, 6, 8, and 13-19 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. (previously cited) in view of Jarett et al. (previously cited), Lichter et al. (US PGPub No. 2010/0009952 – previously cited), and Fatnassi et al. (Powder Technology 2014 255:44-51).
El Kechai et al. teaches the local treatment of otic diseases, such as Meniere’s disease, via the administration of corticosteroid containing hydrogels which provide sustained drug release to the inner ear and reduce the frequency of injections as compared to conventional solution instillations of the drug (see page 249 first column first paragraph). They detail the desire for such hydrogels to be biodegradable and biocompatible as well as the inclusion of dexamethasone as the corticosteroid for application to the round window membrane of the cochlea of the inner ear (see page 249 first column first-third paragraphs). They also detail application to the round window membrane of the cochlea with a syringe via a 30G needle as well as a composition osmolality of 300 mOsm/kg as beneficial (see page 252 first column and second full paragraph; instant claim 14). An administration route to the round window membrane of the cochlea is taught to permit direct visualization of the composition being deposited on the round window of the cochlea (see page 250 second column last partial paragraph; instant claim 6). In addition, El Kechai et al. also teach the dexamethasone present in particle form in the hydrogel material (see page 249 first column third paragraph). They do not detail the specific hydrogel formulation instantly claimed nor the full collection of administration details.
Lichter et al. teach treating Meniere’s disease by local administration of a hydrogel that contains and releases dexamethasone over at least 5 days (see abstract, paragraphs 5, 11, 30, 54, and 64 and examples 28 and 31; instant claims 1, 8, and 19). The hydrogel material is envisioned as transitioning from liquid to gel such that it is applied in liquid form and transitions to gel at the target site (see paragraphs 213-216; instant claim 1). Such compositions may further include a thickener which they describe synonymously with their viscosity enhancing agents (see paragraphs 37 and 43, 191, and 208). They envision applied composition viscosities as ranging from 100 to 1000 mPa•s (cP) (see paragraphs 228-229). Lichter et al. further envision the inclusion of mucoadhesive components that will adhere to the round window membrane of the cochlea (see paragraphs 234-235; instant claim 13). A dye may be included to aid in visualization (see paragraph 37; instant claim 18). They teach application of the composition to the round window membrane of the cochlea via intratympanic injection or surgical routes for direct access (see paragraphs 272-273; instant claim 1). Lichter et al. also teach administering 50 ml as well as volumes up to 90 ml (see example 22).
Jarrett et al. teach an extended release drug delivery hydrogel composition that gels in situ (at target location and at body temperature) (see abstract; instant claim 1). While envisioned for the eye, other deposition sites are also envisioned and include a space or lumen inside a human (see abstract and paragraph 55). They detail administration to a desired locale via a cannula (see paragraph 54; instant claim 1). The hydrogel includes the drug in particle form to facilitate longer term controlled release (see paragraph 25-26). Additionally, the polymer constituent materials are biocompatible and biodegradable in a manner that is controlled via modification to the number of degradable portions (see paragraphs 4 and 109-113). Gelation is detailed to occur within 0.1 to 30 minutes (see paragraph 91; instant claim 1). Reaction chemistries that pair amine functional groups on one hydrogel precursor molecules with N-hydroxysuccinimide groups on another hydrogel precursor molecule are advantageous due to the gelation rate being controlled via pH or concentration (see paragraph 98). They teach the composition as an injectable solution of precursors that maintains their integrity after injection until it gels, which implies that injection/administration occurs within the time duration over which gelation occurs (see paragraph 63). Jarrett et al. generally teach that the reacting components of the gel are sensitive to pH such that reaction rates increase with pH beyond low levels such as 4 to 7 (see paragraph 98). Various buffers to utilize toward this end of raising/controlling the pH are envisioned to include phosphate buffer which has a pH of 5 to 7.5, borate buffer which has a pH of 9 to 12, or triethanolamine buffer which has a pH of 7.5 to 9 (see paragraph 98). A dye may be included to aid in visualization (see paragraph 108; instant claim 18). They additionally disclose that the elasticity of the polymer is increased with increasing polyethylene glycol chain units and point to molecular weight ranges of 2000 to 100,000 to reach this end which implies that the exemplified polymer has a degree of elasticity (see paragraph 90; instant claim 13). In addition, Jarrett et al. assess the release kinetics of a drug from the gel in pH 6.3 buffer and disclose release over more than 5 days which requires the gel to remain present for this duration (see paragraphs 33-34 and figure 11A; instant claim 1). Further, the gels are disclosed as swelling no more than about 50% upon exposure to physiological saline for 24 hours (see paragraph 92; instant claim 15). Jarrett et al. also teach the inclusion of a thixotropic agent, envisioned as hyaluronic acid, that provides little resistance to motion when under shear and forms a gel when static (see paragraph 57). Concentrations of 0.3 to 2.5 wt% were tested and are contemplated to extend to 5 wt% as well (see paragraph 57). Increased viscosity is detailed as useful to retain the composition at a desired tissue locale before the precursors crosslink to form a gel (see paragraph 56). Jarret et al. further exemplify the amine-succinate in situ gelation reaction in a subject to occur over 2 to 5 minutes in a 6.8 pH aqueous mixture of the reactive gel components that also includes 850 kDa hyaluronic acid at approximately 6.4 mg/ml (0.64 wt%) (see example 3, as calculated by the examiner assuming a density of 1 g/ml for part A; instant claim 1). An example details an embodiment composed of water, 9 wt% 4-arm 20,000 molecular weight polyethylene glycol succinimidyl glutarate (first functional polymer), 0.21 wt% trilysine, and a steroid active at about 2 wt% (see example 10; instant claims 1 and 16-17). These components are initially mixed into a liquid form at pH 4.5 to prevent reaction between the reactive terminal groups of the polyethylene glycol chains and the trilysine and then combined with sodium pentaborate to raise the pH and speed reaction (see paragraph 98; instant claim 1). In addition to the steroid active compounds listed in example 10, Jarrett et al. teach and exemplify dexamethasone as an additional steroid active for inclusion in their gel compositions (see paragraph 117 and examples 2-3). The concentrations employed for dexamethasone are 10 wt% and 20 wt% for examples 3 and 2, respectively.
Fatnassi et al. teach that 850 kDa hyaluronic acid at 6 mg/ml (0.6 wt%) has a viscosity of about 50 mPa•s, when measured at a 1000 s-1 shear rate (see page 45 first column fourth paragraph and figure 4). The viscosity increases with increasing concentration where 1 wt% solution has a viscosity of 80 mPa•s, when measured at a 1000 s-1 shear rate (see figure 4).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to treat Meniere’s disease in a subject by administering a composition of Jarrett et al. to the round window membrane of the cochlea in an affected ear of the subject via a cannula, where dexamethasone is included in particle form in their in situ gelling hydrogel. This treatment modality would have been obvious in light of El Kechai et al. who detail the recognized benefit of sustained release hydrogels to provide dexamethasone to these patients with a lessened need for repeated injections compared to conventional treatments. The modification is also obvious in light of Lichter et al. who also teach Meniere’s disease treatment with dexamethasone releasing hydrogels. Identifying a subject with the condition is implicit. A hydrogel composition based on the exemplified embodiment of Jarrett et al. with water, 9 wt% 4-arm 20,000 molecular weight polyethylene glycol succinimidyl glutarate (first functional polymer), 0.21 wt% trilysine, and dexamethasone at about 2 wt% as exemplified that also includes their exemplified 850 kDa thixotropic hyaluronic acid at an envisioned proportion would have been obvious so as to achieve their desired injectability and mechanical integrity upon administration prior to gelation. The composition pH, gelation time, and residence time are result effective variables that are obvious to optimize as a matter of routine experimentation within the range of pH values for buffers they teach to employ, the gelation duration range they teach, and the repeatedly exemplified 2 to 5 minute gelation duration Jarrett et al. illustrate as desirable. Similarly, administration within the gelation duration (e.g., 2 to 5 minutes) is implied by Jarrett et al. would have been obvious. The resulting ranges for these parameters overlap with those instantly claimed, thereby rendering the claimed ranges obvious. “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)” (see MPEP 2144.05). The initial viscosity of the composition prior to gelation also would overlap with that instantly claimed in light of Lichter et al. teaching the instantly claimed range as desirable for an injected otic composition and Fatnassi et al. illustrating the ability of the hyaluronic acid containing preparation to attain a claimed approximate viscosity at the concentrations taught by Jarrett et al. (see MPME 2144.05). The inclusion of a dye and/or a mucoadhesive component also would follow from the teachings of Lichter et al. and Jarett et al. It would also follow to employ the composition osmolality taught by El Kechai et al. as beneficial for such treatments as well as an administration manner that permits visualization of the composition on the round window membrane of the cochlea. Therefore claims 1, 6, 8, and 13-19 are obvious over El Kechai et al. in view of Jarett et al., Lichter et al., and Fatnassi et al.
Claims 1, 6, 8, and 12-19 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarett et al., Lichter et al., and Fatnassi et al. as applied to 1, 6, 8, and 13-19 above, and further in view of Gravett et al. (previously cited).
El Kechai et al. in view of Jarett et al., Lichter et al., and Fatnassi et al. render obvious the limitations of instant claims 1, 6, 8, and 13-19. Jarrett et al. exemplify a hydrogel composition composed of water, 9 wt% 4-arm 20,000 molecular weight polyethylene glycol succinimidyl glutarate, 0.21 wt% trilysine, and a steroid active at about 2 wt% (see instant claim 12). Pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate is not explicitly taught as the 4 arm polyethylene glycol succinimidyl glutarate of Jarrett et al.
Gravett et al. teach pharmaceutical hydrogels that may deliver drugs (see paragraphs 15-16). The hydrogels are composed of polyfunctional polymers, where 4-arm polyethylene glycol varieties are employed that are made from derivatizing pentaerythritol with polyethylene glycol chains of a desired length and terminated by a reactive functional group (see paragraphs 15-16 and 83). These polymers are pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate (see paragraphs 15-16 and 83; instant claim 12).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to apply the dexamethasone containing composition of El Kechai et al. in view of Jarett et al., Lichter et al., and Fatnassi et al., where their 4 arm polyethylene glycol succinimidyl glutarate is structured as pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate as taught by Gravett et al. an included at an exemplified proportion. This choice would have been obvious because Gravett et al. teach pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate was a known particular structure for providing a 4 arm polyethylene glycol succinimidyl glutarate in a reactive pharmaceutical preparation. Therefore claims 1, 6, 8, and 12-19 are obvious over El Kechai et al. in view of Jarett et al., Lichter et al., Fatnassi et al., and Gravett et al.
Claims 1, 6, 8-11, and 13-19 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarett et al., Lichter et al., and Fatnassi et al. as applied to 1, 6, 8, and 13-19 above, and further in view of Carfrae et al. (previously cited).
El Kechai et al. in view of Jarett et al., Lichter et al., and Fatnassi et al. renders obvious the limitations of instant claims 1, 6, 8, and 13-19. Lichter et al. teach administering 50 ml as well as volumes up to 90 ml (see example 22; instant claims 9-10). They further teach monitoring or evaluating progression of the Meniere’s disease with 3 Tesla MRI via endolymphatic hydrops assessment (see paragraph 119). They also teach Meniere’s disease evaluation prior to treatment and periodic evaluation at several time points post-administration that include 1, 2 (about 15 days), 4, and 8 weeks (see paragraphs 485-486; instant claim 11). While gadolinium is envisioned as a contrast agent, intravenous administration is not detailed.
Carfrae et al. teach 3 Tesla delayed contrast MRI for evaluating Meniere’s disease where a gadolinium contrast agent is administered intravenously (see page 501-502). They see that the imaging technique is suitable of visualizing the severity of the condition (see abstract).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to employ 3 Tesla delayed contrast MRI with intravenous gadolinium perform assessments of the severity of Meniere’s disease in the patient in the method of El Kechai et al. in view of Jarett et al., Lichter et al., and Fatnassi et al. This choice would have been obvious because Lichter et al. detail this contrast agent and imaging method to assess Meniere’s disease and Carfrae et al. teach intravenous administration of the contrast agent as effective for permitting characterization of disease severity. It would then follow to conduct the evaluations prior to and at each of the prescribed reevaluation points post-administration as detailed by Lichter et al. Additionally, it would also follow to employ the instillation volume of the gel taught by Lichter et al. Therefore claims 1, 6, 8-11, and 13-19 are obvious over El Kechai et al. in view of Jarett et al., Lichter et al., Fatnassi et al., and Carfrae et al.
Claims 1-6, 8-11, and 13-19 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarett et al., Lichter et al., and Fatnassi et al. as applied to 1, 6, 8, and 13-19 above, and further in view of Lichter B (WO 2011/049954 – previously cited).
El Kechai et al. in view of Jarett et al., Lichter et al., and Fatnassi et al. render obvious the limitations of instant claims 1, 6, 8, and 13-19. Lichter et al. teach intratympanic injection via a syringe and needle which is inserted through the tympanic membrane (see paragraphs 143 and 272; instant claim 3). They additionally teach the application of treatment composition during surgical procedures such as mastoidectomy (see paragraph 277; instant claim 4).
Lichter B teaches intratympanic administration of a therapeutic dosage form to the round window membrane of the cochlea of the inner ear (see abstract and paragraphs 2 and 39). Here they detail such administration via needle or cannula with a 25 to 31 gauge size (see paragraph 36). In addition, they detail avoiding the ossicles when administering the composition to the round window membrane of the cochlea (see paragraph 33; instant claim 5).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to employ a cannula sized as taught by Lichter B in the method of El Kechai et al. in view of Jarett et al. and Lichter et al. This modification would have been obvious as simple substitution of one known component for another in order to yield a predictable outcome. It would then follow to administer the composition via intratympanic injection, as a part of mastoidectomy surgery, or in a manner that avoids the ossicles as detailed by Lichter et al. or Lichter B. Therefore claims 1-6, 8-11, and 13-19 are obvious over El Kechai et al. in view of Jarett et al., Lichter et al., Fatnassi et al., and Lichter B.
Claims 1-11 and 13-19 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarett et al., Lichter et al., Fatnassi et al., and Lichter B as applied to 1-6, 8-11, and 13-19 above, and further in view of Donovan (previously cited).
El Kechai et al. in view of Jarett et al., Lichter et al., Fatnassi et al., and Lichter B render obvious the limitations of instant claims 1-6, 8-11, and 13-19, where a cannula is employed to intratympanically administer the gelling composition. The use of an endoscope is not detailed.
Donavan teaches intratympanic administration of a composition to the inner ear (see paragraph 430. the detail visualizing the tympanic membrane and making and incision through which injection/instillation of the composition can occur (see paragraph 61-62 and 64-68; instant claim 7).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to employ an endoscope to permit access and visualization of the round window treatment site for intratympanic administration of the composition of El Kechai et al. in view of Jarett et al., Lichter et al., Fatnassi et al., and Lichter B as a known procedure for facilitating intratympanic administration. Therefore claims 1-6, 8-11, and 13-19 are obvious over El Kechai et al. in view of Jarett et al., Lichter et al., Fatnassi et al., Lichter B, and Donovan.
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.
The following are provisional nonstatutory double patenting rejections because the patentably indistinct claims have not in fact been patented.
Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-19 of copending Application No. 19/530028 (reference application) in view Lichter et al.
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims recite an injector system for administering a composition of instant claim 1 with the same proportions of dexamethasone, first functional polymer, and trilysine with the instantly claimed properties to treat an otic disease or disorder. The gel formation and routes of administration to a round window of the cochlea of a subject are the same. Also, both sets of claims recite the same instillation volume as well as pre- and post- administration MRI based evaluation of endolymphatic hydrops or perilymphatic enhancement. The copending claims do not explicitly teach treating Meniere’s disease, cannula delivery or an initial viscosity.
Lichter et al. teach treating Meniere’s disease by local administration of a hydrogel that contains and releases dexamethasone over at least 5 days (see abstract, paragraphs 5, 11, 30, 54, and 64 and examples 28 and 31). The hydrogel material is envisioned as transitioning from liquid to gel such that it is applied in liquid form and transitions to gel at the target site (see paragraphs 213-216; instant claim 1). Such compositions may further include a thickener which they describe synonymously with their viscosity enhancing agents (see paragraphs 37 and 43, 191, and 208). They envision applied composition viscosities as ranging from 100 to 1000 mPa•s (cP) (see paragraphs 228-229). Lichter et al. further envision the inclusion of mucoadhesive components that will adhere to the round window membrane of the cochlea (see paragraphs 234-235).
Lichter B teaches intratympanic administration of a therapeutic dosage form to the round window membrane of the cochlea of the inner ear (see abstract and paragraphs 2 and 39). Here they detail such administration via needle or cannula with a 25 to 31 gauge size (see paragraph 36). In addition, they detail avoiding the ossicles when administering the composition to the round window membrane of the cochlea (see paragraph 33; instant claim 5).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to use the system of the copending claims as intended to administer the composition they recite via the steps they recite because that is the intended purpose of the product. Facilitating instillation via a cannula with the injector in light of Lichter B would have been obvious as the application of the same technique to a similar method in order to yield the same improvement. It also would have been obvious to adjust the viscosity for injection with a thickener or viscosity enhancing agent to attain a viscosity indicated by Lichter et al. as useful for such otic treatment compositions. More specifically, treating Meniere’s disease in light of Lichter et al. would have been obvious because this condition is treated with a similar gel forming composition with the same active applied to the same location. Cannula application to the treatment site would follow. Therefore claims 1-19 are obvious over claims 1-4 and 6-19 of copending Application No. 19/463990 in view of Lichter et al. and Lichter B
Claims 1-3, 5-8, 12-13, and15-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-16 of copending Application No. 19/644801 (reference application) in view Lichter et al. and Lichter B.
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite administering a composition of instant claim 1 with the same proportions of an anti-inflammatory active that can be dexamethasone, first functional polymer, and trilysine with the instantly claimed properties. The gel formation and routes of administration to a round window membrane of the cochlea of a subject are the same. They do not explicitly teach treating Meniere’s disease with the method.
Lichter et al. teach treating Meniere’s disease by local administration of a hydrogel that contains and releases dexamethasone over at least 5 days (see abstract, paragraphs 5, 11, 30, 54, and 64 and examples 28 and 31). The hydrogel material is envisioned as transitioning from liquid to gel such that it is applied in liquid form and transitions to gel at the target site (see paragraphs 213-216; instant claim 1). Such compositions may further include a thickener which they describe synonymously with their viscosity enhancing agents (see paragraphs 37 and 43, 191, and 208). They envision applied composition viscosities as ranging from 100 to 1000 mPa•s (cP) (see paragraphs 228-229). Lichter et al. further envision the inclusion of mucoadhesive components that will adhere to the round window membrane of the cochlea (see paragraphs 234-235). A dye may be included to aid in visualization (see paragraph 37). They teach administering 50 ml as well as volumes up to 90 ml (see example 22).
Lichter B teach intratympanic administration of a therapeutic dosage form to the round window membrane of the cochlea of the inner ear (see abstract and paragraphs 2 and 39). Here they detail such administration via needle or cannula with a 25 to 31 gauge size (see paragraph 36). In addition, they detail avoiding the ossicles when administering the composition to the round window membrane of the cochlea (see paragraph 33; instant claim 5).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to practice the method of copending claims in order to treat Meniere’s disease in light of Lichter et al. because this condition is treated with a similar gel forming composition with the same active applied to the same location. It also would have been obvious to adjust the viscosity for injection with a thickener or viscosity enhancing agent to attain a viscosity indicated by Lichter et al. as useful for such otic treatment compositions. Cannula application to the treatment site and ossicle avoidance would follow in light of Lichter B as would dye inclusion and instillation volume in light of Lichter et al. Therefore claims 1-3, 5-8, 12-13, and 15-19 are obvious over claims 1-12 and 14-16 of copending Application No. 19/644801 in view of Lichter et al. and Lichter B.
Claims 1-3, 5-13, and 15-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-16 of copending Application No. 19/644801 in view of Lichter et al. and Lichter B as applied to 1-3, 5-8, 12-13, and 15-19 above, and further in view of Carfrae et al.
Claims 1-12 and 14-16 of copending Application No. 19/644801 in view of Lichter et al. and Lichter B renders obvious the limitations of instant claims 1-3, 5-8, 12-13, and 15-19. Lichter et al. teach administering 50 ml as well as volumes up to 90 ml (see example 22; instant claims 9-10). They further teach monitoring or evaluating progression of the Meniere’s disease with 3 Tesla MRI via endolymphatic hydrops assessment (see paragraph 119). They teach Meniere’s disease evaluation prior to treatment and periodic evaluation at several time points post-administration that include 1, 2 (about 15 days), 4, and 8 weeks (see paragraphs 485-486). While gadolinium is envisioned as a contrast agent, intravenous administration is not detailed.
Carfrae et al. teach 3 Tesla delayed contrast MRI for evaluating Meniere’s disease where a gadolinium contrast agent is administered intravenously (see page 501-502). They see that the imaging technique is suitable of visualizing the severity of the condition (see abstract).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to employ 3 Tesla delayed contrast MRI with intravenous gadolinium perform assessments of the severity of Meniere’s disease in the patient in the modified method of the copending claims. This choice would have been obvious because Lichter et al. detail this contrast agent and imaging method to assess Meniere’s disease and Carfrae et al. teach intravenous administration of the contrast agent as effective for permitting characterization of disease severity. It would then follow to conduct the evaluations prior to and at each of the prescribed reevaluation points post-administration as detailed by Lichter et al. Additionally, it would also follow to employ the instillation volume of the gel taught by Lichter et al. Therefore claims 1-3, 5-13, and 15-19 are obvious overclaims 1-12 and 14-16 of copending Application No. 19/644801 in view of Lichter et al., Lichter B, and Carfrae et al.
Claims 1-3, 5-8, and 12-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-16 of copending Application No. 19/644801 in view Lichter et al. and Lichter B as applied to 1-3, 5-8, 12-13, and 15-19 above, and further in view of El Kechai et al.
Claims 1-12 and 14-16 of copending Application No. 19/644801 in view of Lichter et al. and Lichter B renders obvious the limitations of instant claims 1-3, 5-8, 12-13, and 15-19. The osmolality of the composition is not detailed.
El Kechai et al. teach the local treatment of otic diseases, such as Meniere’s disease, via the administration of corticosteroid containing hydrogels which provide sustained drug release to the inner ear and reduce the frequency of injections as compared to conventional solution instillations of the drug (see page 249 first column first paragraph). They detail the desire for such hydrogels to be biodegradable and biocompatible as well as the inclusion of dexamethasone as the corticosteroid for application to the round window membrane of the cochlea of the inner ear (see page 249 first column first-third paragraphs). They detail application to the round window membrane of the cochlea with a syringe via a 30G needle as well as a composition osmolality of 300 mOsm/kg as beneficial (see page 252 first column and second full paragraph).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to employ the osmolality detailed by El Kechai et al. in the modified copending claim because it was detailed as suitable for instillation on to the round window membrane of the cochlea of the inner ear. Therefore claims 1-3, 5-8, and 12-19 are obvious over claims 1-12 and 14-16 of copending Application No. 19/644801 in view of Lichter et al., Lichter B, and El Kechai et al.
Response to Arguments
Applicant's arguments filed July 21, 2026 have been fully considered. In light of the amendment to the claims, the provisional double patenting rejection over US application No. 19/463990 is withdrawn. The remaining rejections are new, modified grounds of rejection to address the new limitations. Arguments concerning the maintained rationales are not persuasive and are addressed below.
The applicant argues that the rejections ignore the interrelationship of the claimed pH and gelation time. To the contrary, the connection between the gelation kinetics with concentration and pH for amine-succinimide reactivity was already recognized in the prior art, as noted by Jarrett et al. They were not alone in recognizing this connection. Sawhney et al. also discuss the reactivity of 4-arm N-hydroxysuccinimide PEG reacted with a trilysine salt where gelation can occur in less than 5 seconds at pH 9.4 and in about 30 seconds at pH 8.8 which is again illustrative of the known correlation between pH and gelation duration for this chemistry (see US PGPub No. 2008/0187568 paragraphs 89-90). The applicant has not provided any new guidance concerning the correlation of pH and gelation time for any particular disclosed pairing of functional polymer with trilysine in a claimed composition that also includes dexamethasone and the initial viscosity that is now recited. At the same time, the existence of the prior art composition with concentrations for a functional polymer and trilysine in the instantly claimed range and the overlapping pH range and associated gelation times the prior art also teaches is highly suggestive of the obviousness of the recited composition, given the capabilities of the artisan of ordinary skill.
The applicant also argues that the 6.8 pH taught by Jarrett et al. does not overlap with the instantly claimed pH. To be clear, the instant claims recite an approximate range of about 5.5 to about 6.0 where the term “about” has not been given a limiting definition that precludes a value of 6.8. Additionally, the applicant’s own examples do not provide compositions that undergo gelation within 2 to 8 minutes at a pH between 5.5. and 6. If the instant invention were viewed as rigidly as the applicant argues, the closest of their examples to the composition of the instant claims would appear to fall short of such requirements. Furthermore, Jarrett et al. repeatedly comment on and teach that increasing the pH of the composition beyond a pH of about 4 increases the gelation rate and specifies the pH range over which the artisan should work, including the buffers to employ to achieve them, as well as the range of gelation durations they contemplate. These pH ranges embrace or overlap the claimed range which renders them obvious and the increase in pH is known to shorten the gelation duration (increase gelation rate) which makes result effective variables that are also obvious to optimize as a matter of routine experimentation.
The applicant argues that “design choice” is not a valid basis for obviousness in the absence of a prior art publication disclosing the claim element. This argument is not based upon the fact pattern of the rejections of the prior office action. The rejections did not rely upon a “design choice” rationale and the cited prior art teaches a composition with claimed components at claimed concentrations as well as overlapping ranges for gelation times and pH. The rejection instead relied upon these latter parameters being result effective variables which is a valid rationale to support obviousness for routine optimization from a known product by the person of ordinary skill to reach another workable product (see MPEP 2144.05 (II)).
The applicant further argues that Jarret et al. teach away from the claimed combination because they state that an acidic pH delays or prevents crosslinking. When this discussion is considered in the context in which it is provided, Jarrett et al. further detail adding a basic buffer that they already discuss as being provided as a way to control pH in order to control gelation rate (see example 13 and paragraph 98). Their statement that “[a]n advantage of an NHS-amine reaction is that the reaction kinetics are favorable, but the gelation rate may be adjusted through pH or concentration… reaction rate of these groups may be delayed by keeping these solutions at lower pH(4-7)” is a clear indication of the understanding. It indicates their understanding that the composition with 4-arm NHS PEG paired with the amine trilysine they exemplified had a gelation rate controllable by raising the pH via the addition of a basic pH borate buffer to an acidic pH 4.5 solution of the two reactive precursors (see example 13 and paragraph 98).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Jarrett et al., link a pH increasing from 4 into a basic range with an increasing rate of gelation for the polymer system they exemplify that is also embraced by the instant claims. Thus, no hindsight reasoning was employed or necessary to identify pH and gelation duration as result effective variables for the polymer system of Jarrett et al.
Acknowledgment of the provisional double patenting rejections is noted.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/CARALYNNE E HELM/Examiner, Art Unit 1615
/MELISSA S MERCIER/Primary Examiner, Art Unit 1615
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