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 .
Terminal Disclaimer
The terminal disclaimers filed on July 31, 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US Application No. 19/459988, US Application No. 19/644801, US Application No. 19/530028 have been reviewed and is accepted. The terminal disclaimers have been recorded.
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 1-25 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.
Claims 1, 18, and 21 recite a crosslinking polymer composition as a component of a recited treatment gel. In claims 1 and 21, the crosslinking polymer composition consists of a first functional polymer, a crosslinker, sodium phosphate, dye, and water, each present within a recited approximate range, as well as a dye and water. This combination of components has a pH of about 5.5 to about 6.0 and is recited to have (embraces) a gelation time of about 2 minutes to about 8 minutes at a temperature of about 37⁰C (see below rejection under section (b) of this statute for further elaboration on gelation duration). In claim 18, the crosslinking polymer composition is further defined such that the functional polymer is pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate and the crosslinker is trilysine.
A number of aspects of the cross-linking polymer composition affect gelation. The identity and relative amounts of the functional groups on the first functional polymer and crosslinker in claims 1 and 21 have an impact on the gelation time. The first functional polymer and crosslinker concentrations, reaction mixture pH and reaction mixture temperature also influence the gelation time. All of these are parameters that must be selected for each embodiment and, in combination, result in various gelation times. In addition, the scope of the physical changes that indicates that gelation has occurred is broad. 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). Jarrett et al. (previously cited) discuss gelation as when a cross-linking polymer 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).
The disclosure does not provide an example of the claimed cross-linking polymer composition where the first functional polymer and crosslinker are identified and present at claimed proportions The first functional polymer, instantly claimed, can have any number of any type of functional groups that are reactive with functional groups in the instantly claimed crosslinker. The applicant cites US Patent 7,332,566 (see IDS) by Pathak et al. as teaching envisioned reaction systems (see specification page 52 lines 25-27). They discuss 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 (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 trilysine 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 (PEG) 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 time 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. Instant example 11 provides the closest teaching of a composition with the required functionality, yet the function is only embraced by the approximate nature of the upper end of the recited pH range. This composition does not include dexamethasone, dye, the concentrations of trilysine and the generically described functional polymer, or the identity of the functional polymer. Instant example 1 mentions a commercial product from Covidien as the source of PEG ester as a first functional polymer and trilysine as a crosslinker employed in the examples; however the product employed is not clearly identified. The applicant provided product insert for DuraSeal® from Covidien that also employs a PEG-ester and trilysine in a reactive system disclosed its PEG ester concentration in the composition to be 3.87 wt% with a 0.211 wt% trilysine concentration (see DuraSeal, “Dual Sealant System tender Package – page 13 previously cited in IDS). Thus, even if the DuraSeal® proportions were employed, the functional polymer concentration would only be on the periphery of the claim scope. 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.
Trollsas et al. (US PGPub No. 2002/0042473) illustrate a first functional polymer and crosslinker that provide reactive succinimidyl and amine groups, respectively. A shift in pH of reaction mixture with 2.5 wt% of both first functional polymer and crosslinker from 6.9 to 7.2 lowers gelation time from 10-15 minutes to less than 5 minutes at 45⁰C (see table 5). An increase in temperature of a reaction mixture with 2.5 wt% of both first functional polymer and crosslinker at a pH of about 6.6 from 37⁰C to between 40⁰C and 50⁰C lowers the gelation time from 20-25 minutes down to about 5 minutes (see example 5). An increase in pH and component concentration both resulted in reduced gelation time ranging from 5 second to more than 90 minutes (see example 6). Their embodiment that is clearly within the instant claim scope with a pH of 6 and gelation time between 2 and 8 minutes had proportions of the crosslinker and first functional polymer of 20 wt%. More peripheral pH and gelation times of pH 7 and 6 minute gelation times occurred in composition with first functional polymer at 5 wt% or 10 wt% had crosslinker proportions outside the claim scope that were also at 5 wt% and 10 wt% (see example 6). Thus the prior art does not suggest that the details of the claimed composition parameter value/choice combination that are absent from the disclosure were implicit or conventional.
There is no discussion provided by the disclosure aligning structural features of a composition in regard to the identity of the functional polymer and corresponding crosslinker, that when included in the composition at the recited concentrations and recited pH, is illustrative of compositions that meet the claimed gelation time constraints. In the context of the more specifically recited crosslinker and/or functional polymer of instant claims 13-14, 18, and 23, there is no disclosed connection between this variety of functional polymer and crosslinker with the currently claimed composition functionality. As a result, there is an inadequate structure-function correlation for the claimed method, and 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.
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 18-25 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.
It is unclear whether the recitation of claim 18 stating “said cross-linking polymer composition has a pH of about 5.5 to about 6.0 to provide a gelation time of about 2 minutes to about 8 minutes at a temperature of about 37 °C” in claims 18 and 21 means that 1) a gelation time of about 2 minutes to about 8 minutes at a temperature of about 37 °C is a consequence of the composition having a pH of about 5.5 to about 6.0 or 2) an additional structural characteristic (e.g., component concentration combination, etc.) is required, beyond meeting the pH limitation, in order to have a gelation time of about 2 minutes to about 8 minutes at a temperature of about 37 °C.
Claims that are rejected, but are not explicitly elaborated upon, are also indefinite because they depend from an indefinite claim and do not add clarity.
Claim Interpretation
Claims 1, 18, and 21 recite a treatment gel with different language that delineate different scopes of compositions for their recited methods.
Claim 1 recites “about 40 ml to about 60 ml of a treatment gel…remains...for a residence time of at least 5 days, wherein said treatment gel 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 37⁰C said cross-linking polymer composition consisting of: (i) a first functional polymer in an amount of about 5% to about 15% by weight of the polymer composition, (ii) a crosslinker in an amount of about 0.05% to about 0.6% by weight of the polymer composition so as to provide a gel formation reaction with said first functional polymer, (iii) sodium phosphate in an amount of about 0.01% to about 3.0% of the polymer composition, (iv) water, and (v) a dye…”[emphasis added].
The claim recites a treatment gel composition with open language, where a cross-linking polymer composition is one of the treatment gel constituents
The cross-linking polymer composition is recited with closed language where it has a pH in a particular range and a gelation time within a particular range at a range of temperatures.
Since the treatment gel includes components in addition to the cross-linking polymer composition, the functional properties (e.g., gelation duration), components (e.g., added drug, acid, base, etc.), and component proportions of the treatment gel are broader in scope than the cross-linking polymer composition.
Claim 18 recites “about 40 ml to about 60 ml of a treatment gel…the treatment gel remains at the round window membrane of the cochlea for a residence time of at least 14 days, said treatment gel consisting of: (a) dexamethasone present in an amount of about 6% by weight of said treatment gel, and (b) a cross-linking polymer composition consisting of: (i) a first functional polymer of pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate in an amount of about 5% to about 15% by weight of the polymer composition, (ii) a crosslinker of trilysine, or a salt thereof, in an amount of about 0.05% to about 0.6% by weight of the polymer composition so as to provide a gel formation reaction with said first functional polymer, (iii) sodium phosphate in an amount of about 0.01% to about 3.0% of the polymer composition, (iv) water, and (v) a dye, wherein said cross-linking polymer composition has a pH of about 5.5 to about 6.0 to provide a gelation time of about 2 minutes to about 8 minutes at a temperature of about 37 °C…” [emphasis added].
The treatment gel composition is recited with closed language, where the cross-linking polymer composition and dexamethasone are its only components.
The claim recites the cross-linking composition with closed language, where it has a pH in a particular range and a gelation time within a particular range at a range of temperatures.
The treatment gel is constrained to only be composed of the recited ingredients at the recited approximate proportions and only differs in composition from the cross-linking polymer composition in regard to the presence of the dexamethasone. While the limitations concerning gelation temperature are recited for the cross-linking polymer composition, the treatment gel may only differ in function from the cross-linking polymer composition to the degree that the presence of the dexamethasone induces.
Claim 21 recites “about 40 ml to about 60 ml of a treatment gel…the treatment gel remains at the round window membrane of the cochlea for a residence time of at least 14 days, said treatment gel consisting of: (a) dexamethasone, and (b) a cross-linking polymer composition consisting of: (i) a first functional polymer in an amount of about 5% to about 15% by weight of the polymer composition, (ii) a crosslinker in an amount of about 0.05% to about 0.6% by weight of the polymer composition so as to provide a gel formation reaction with said first functional polymer, (iii) sodium phosphate in an amount of about 0.01% to about 3.0% of the polymer composition, (iv) water, and (v) a dye, wherein said cross-linking polymer composition has a pH of about 5.5 to about 6.0 to provide a gelation time of about 2 minutes to about 8 minutes at a temperature of about 37 °C…” [emphasis added].
The treatment gel composition is recited with closed language, where the cross-linking polymer composition and dexamethasone are its only components.
The claim recites the cross-linking composition with closed language, where it has a pH in a particular range and a gelation time within a particular range at a range of temperatures.
The treatment gel is constrained to only be composed of the recited ingredients at the recited approximate proportions and only differs in composition from the cross-linking polymer composition in regard to the presence of the dexamethasone. While the limitations concerning gelation temperature are recited for the cross-linking polymer composition, the treatment gel may only differ in function from the cross-linking polymer composition to the degree that the presence of the dexamethasone induces.
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 1-5, 7-9, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. (previously cited) in view of Jarrett et al. (previously cited), Lichter et al. (US PGPub No. 2010/0009952 – previously cited), and Lichter B (WO 2011/049954 – previously cited).
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 otic 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 16). An administration route to the round window membrane of the cochlea is taught that permits direct visualization of the composition being deposited on the round window of the cochlea (see page 250 second column last partial paragraph; instant claim 1). 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 otic conditions, such as 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). They also exemplify 30 days (see example 28). 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). They also teach the gel as a crosslinked polymer gel (see paragraph 231). Lichter et al. further envision the inclusion of mucoadhesive components that will adhere the composition to the round window membrane of the cochlea (see paragraphs 234-235; instant claim 1). Osmolality is from about 200 to 800 mOsm/kg and may be attained by selecting the proper salt and tonicity agent proportions (see paragraphs 194-195; instant claim 16). 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). They additionally teach the application of treatment compositions during surgical procedures such as mastoidectomy (see paragraph 277; instant claim 4). Lichter et al. also teach administering 50 ml as well as volumes up to 90 ml (see example 22; instant claim 5).
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).
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). A dye may be included to aid in visualization (see paragraph 108; instant claim 18). Additionally, the polymer constituent materials are biocompatible and biodegradable in a manner that is controlled via modification to the number of degradable portions such that a desired persistence duration is achieved (see paragraphs 4 and 109-113). They detail the gel lasting days to months via control of degradation rate as well as the gel persisting past the duration of drug release (see paragraphs 58-59 and 110) Jarrett et al. teach that gelation occurs within 0.1 to 30 minutes (see paragraph 91; instant claim 1). Reaction chemistries that pair amine functional groups on one set of hydrogel precursor molecules with NHS groups on another set of hydrogel precursor molecules are taught as advantageous due to the gelation rate being controlled via pH or concentration (see paragraph 98). 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). 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). 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). Jarret et al. further exemplify the amine-succinimidyl 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 (see example 3, as calculated by the examiner assuming a density of 1 g/ml for part A; instant claim 1). Example 10 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 in 1 mg/ml (0.1 wt%) sodium phosphate dibasic to prevent reaction between the reactive terminal NHS groups of the polyethylene glycol chains and the amine groups of 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 in examples 2 and 3 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. In addition, Jarrett et al. assess the release kinetics of a drug from the gel in pH 6.3 buffer and illustrate gel persistence over more than 14 days (see paragraphs 33-34 and figures 11A and 12A; instant claim 1).
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 El Kechai et al. in light of Jarrett et al. and Lichter et al. by administering a version of the example 10 composition of Jarrett et al. to the round window membrane of the cochlea in a Meniere’s disease affected ear of a subject via an otic cannula, where dexamethasone is included in particle form. The dexamethasone containing Jarrett et al. composition provides treatment gel composed of sodium tetraborate, dexamethasone as a steroidal compound, and a cross-linking polymer gel composition consisting of 9 wt% first functional polymer/4PEG-SG, 0.21 wt% crosslinker trilysine, 0.05 wt% sodium phosphate monohydrate, and water. The inclusion of a dye and/or a mucoadhesive component would follow from the teachings of Lichter et al. and Jarrett et al. and be considered members of the cross-linking polymer composition and treatment gel, respectively. Their presence is obvious as the application of the same technique to a similar product in order to yield the same improvement. It would then follow to employ the composition osmolality taught by El Kechai et al. and/or Lichter et al. as beneficial for such treatments. The composition pH, gelation time, and residence time are result effective variables that are obvious to optimize as a matter of routine experimentation. The resulting ranges for these parameters then 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 intratympanic treatment of Meniere’s disease 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 that transition from liquid to gel. Administration in a manner that permits visualization of the composition on the round window membrane of the cochlea would then follow from the direction of El Kechai et al. Additionally, it would have been obvious to employ an (otic) cannula sized as taught by Lichter B in the modified method of El Kechai et al. to administer a volume as detailed by Lichter er al. as the simple substitution of one known component for another in order to yield a predictable outcome. It would also 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 because they teach these routes as suitable for the administration of otic hydrogels. Therefore claims 1-5, 7-9, and 15-17T are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., and Lichter B.
Claims 1-5, 7-9, and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarrett et al., Lichter et al., and Lichter B as applied to claims 1-5, 7-9, and 15-18 above, and further in view of Gravett et al. (previously cited).
El Kechai et al. in view of Jarrett et al., Lichter et al., and Lichter B render obvious the limitations of instant claims 1-5, 7-9, and 15-17. The administered composition of Jarrett et al. includes 4-arm 20,000 molecular weight polyethylene glycol succinimidyl glutarate (see instant claim 1). 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 claims 13-14).
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 Jarrett et al., Lichter et al., and Lichter B, where their 4 arm polyethylene glycol succinimidyl glutarate is structured as pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate as taught by Gravett et al. This choice would have been obvious because Gravett 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 1-5, 7-9, and 13-17 are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, and Gravett et al.
Claims 1-5, 7-12, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarrett et al., Lichter et al., and Lichter B as applied to claims 1-5, 7-9, and 15-17 above, and further in view of Carfrae et al. (previously cited).
El Kechai et al. in view of Jarrett et al., Lichter et al., and Lichter B render obvious the limitations of instant claims 1-5, 7-9, and 15-17. Lichter et al. 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 claims 10-12). 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 Jarrett et al. Lichter et al., and Lichter B. 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 1-5, 7-12, and 15-17 are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, and Carfrae et al.
Claims 1-9 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarrett et al., Lichter et al., and Lichter B as applied to claims 1-5, 7-9, and 15-17 above, and further in view of Donovan (previously cited).
El Kechai et al. in view of Jarrett et al. and Lichter et al. render obvious the limitations of instant claims 1-5, 7-9, and 15-17, where an otic 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. They detail visualizing the tympanic membrane with an endoscope and making an incision through which injection/instillation of the composition can occur (see paragraph 61-62 and 64-68; instant claim 6).
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 Jarrett et al., Lichter et al., and Lichter B as a known procedure for facilitating intratympanic administration. Therefore claims 1-9 and 15-17 are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, and Donovan.
Claims 1-9 and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, and Donavan et al. as applied to claims 1-9 and 15-18 above, and further in view of Gravett et al.
El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, and Donavan et al. render obvious the limitations of instant claims 1-9 and 15-17. The administered composition of Jarrett et al. includes 4-arm 20,000 molecular weight polyethylene glycol succinimidyl glutarate (see instant claim 1). 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 claims 13-14).
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 Jarrett et al., Lichter et al., Lichter B, and Donavan 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. This choice would have been obvious because Gravett 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 1-9 and 13-17 are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Donavan et al., and Gravett et al.
Claims 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Donavan et al., and Gravett et al. as applied to claims 1-9 and 13-17 above, and further in view of Carfrae et al.
El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Donavan et al., and Gravett et al. render obvious the limitations of instant claims 1-9 and 13-17. Lichter et al. 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 claims 10-12). 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 Jarrett et al., Lichter et al., Lichter B, Donavan et al., and Gravett 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 1-17 are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Donavan et al., Gravett et al., and Carfrae et al.
Claims 1-5, 7-9, and 13-25 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., Promega® Protocols & Applications Guide “Buffers for Biochemical Reactions” 2012 pages 1-5 (henceforth Promega® reference), and Austin et al. (US Patent No. 5,159,096) as evidenced by Alter et al. (US Patent No. 5,753,094).
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 otic 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). An administration route to the round window membrane of the cochlea is taught that permits direct visualization of the composition being deposited on the round window of the cochlea (see page 250 second column last partial paragraph; instant claims 1, 18, and 21). 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 16). 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 otic conditions, such as 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, 18, and 21-22). They also exemplify 30 days (see example 28). 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 claims 1-2, 18-19, 21, and 24). They also teach the gel as a crosslinked polymer gel (see paragraph 231). Lichter et al. further envision the inclusion of mucoadhesive components that will adhere the composition to the round window membrane of the cochlea (see paragraphs 234-235; instant claim 1). Dexamethasone is present at 0.1 to 10 wt%, where a concentration of 4.5 wt% (about 6 wt%) is exemplified (see paragraph 383 and claim 1; instant claims 7, 9, 18, and 22). Osmolality is from about 200 to 800 mOsm/kg and may be attained by selecting the proper salt and tonicity agent proportions (see paragraphs 194-195; instant claim 16). 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). They additionally teach the application of treatment compositions during surgical procedures such as mastoidectomy (see paragraph 277; instant claim 4). Lichter et al. also teach administering 50 ml as well as volumes up to 90 ml (see example 22; instant claim 5).
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; instant claims 2-3, 19, and 24). 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).
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). A dye may be included to aid in visualization (see paragraph 108; instant claim 18). Additionally, the polymer constituent materials are biocompatible and biodegradable in a manner that is controlled via modification to the number of degradable portions such that a desired persistence duration is achieved (see paragraphs 4 and 109-113). They detail the gel lasting days to months via control of degradation rate as well as the gel persisting past the duration of drug release (see paragraphs 58-59 and 110). 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 15). 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 17). Jarrett et al. teach that gelation occurs within 0.1 to 30 minutes (see paragraph 91; instant claims 1, 18, and 21). Reaction chemistries that pair amine functional groups on one set of hydrogel precursor molecules with NHS groups on another set of hydrogel precursor molecules are taught as advantageous due to the gelation rate being controlled via pH or concentration (see paragraph 98). 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). Jarret et al. further exemplify the amine-succinimidyl 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 (see example 3, as calculated by the examiner assuming a density of 1 g/ml for part A; instant claim 1). Example 10 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, 13-14, 18, and 21-23). These components are initially mixed into a liquid form at pH 4.5 to prevent reaction between the reactive terminal NHS groups of the polyethylene glycol chains and the amine groups of 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 in examples 2 and 3 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. In addition, Jarrett et al. assess the release kinetics of a drug from the gel in pH 6.3 buffer and illustrate gel persistence over more than 14 days (see paragraphs 33-34 and figures 11A and 12A; instant claim 1).
Trollsas et al teach in situ crosslinking gels for drug delivery (see abstract and paragraph 146). They detail a 4-arm PEG with a terminal succinimidyl group on each arm reacting with a polyamine which employes the amine-succinimidyl (amine-NHS) reaction chemistry also relied upon by Jarrett et al. (see paragraphs 21, 24, and 113-115). Trollsas et al. further teach the 4-arm PEG with a terminal succinimidyl group on each arm as pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate (see figure 1 and paragraphs 21 and 114; instant claims 13-14, 18, and 23). They exemplify the combination of a solution composed only of such a 4-arm PEG in 6.6 pH 0.2M phosphate buffer with a solution of polylysine in phosphate buffer (PBS) (see paragraph 202). Another example with a tetra succinimidyl functional PEG and tetra amine functional PEG combines the two polymers in water and PBS, noting no other required additions (see paragraphs 202-205). Trollsas et al. also illustrate that the gelation rate of the amine-succinimidyl reactive system increases with concentration of the reactants (see example 6).
The Promega® reference teaches 0.1M phosphate buffer diluted from an 0.2 M stock as a common buffer and lists a pH 6.8 version produced from the three component combination of water, sodium phosphate monobasic, and sodium phosphate dibasic (see page 15-4, especially section C). They also detail combinations of these three ingredients into phosphate buffers that attain a pH level ranging from 5.8 to pH 8 (see page 15-4 section C). Austin et al. detail that sodium phosphate monobasic provides a pH of 4.1 and sodium phosphate dibasic provides a pH of 8.4 (see column 9 lines 21-23).
It would have been obvious to the artisan of ordinary skill in the art at the time of filing of the invention to administer a composition of Jarrett et al. to the round window membrane of the cochlea in a Meniere’s disease affected ear of a subject via an otic cannula, where dexamethasone is included in particle form in the hydrogel, when considered along with El Kechai et al. and Lichter et al.
Regarding the gel composition, Jarrett et al. exemplify a composition consisting of a two part mixture where part 1 consists of water, 4-arm 20,000 molecular weight polyethylene glycol succinimidyl glutarate (4PEG-SG; first functional polymer), trilysine (crosslinker), a steroid active and sodium phosphate monobasic that gives a pH of 4.5 and part 2 consists of water and sodium tetraborate which gives a basic pH of about 10 (see Alter et al. column 4 lines 43-45). When combined, the result is a cross-linking polymer composition consisting of 9 wt% first functional polymer/4PEG-SG, 0.21 wt% crosslinker trilysine, about 0.05 wt% sodium phosphate monohydrate, 2 wt% steroidal compound, water, and sodium tetraborate. The exemplified concentrations for the envisioned steroidal compounds in examples 2-3 and 10 of Jarrett et al. generate a range of 2 to 20 wt% in the composition while Lichter et al. detail a range of 0.1 to 10 wt% and 4.5 wt5 (about 6 wt%) example for dexamethasone in otic conditions. As applied to the dexamethasone loading, these ranges and proportions meet or embrace the instantly claimed limitation for the dexamethasone proportion, thereby rendering the claimed range obvious (see MPEP 2144.05; instant claims 7, 9, 18, and 22). The selection of pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate, taught by Trollsas et al., for the 4PEG-SG would have been obvious. This choice would have been obvious because Trollsas 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 similarly structured amine-succinimidyl reactive drug delivery preparation. The exemplified gelation pH of 6.8 that yields gelation within 2 to 5 minutes, detailed by Jarrett et al. for their amine-succinimidyl reaction system, indicates a desired zone in which to operate and around which to optimize because these parameters are result effective variables. The teaching of Jarrett et al. of sodium phosphate buffer as an envisioned avenue to attain a desired gelation pH, paired with the illustration by Trollsas et al. of a similar PEG based tetra-arm-tetra amine-succinimidyl reaction system with only water and phosphate buffer controlling pH to nearly the same value, renders the use of a sodium phosphate buffer to generate the gelation pH in the gel composition of Jarrett et al. obvious to the artisan of ordinary skill. The modification is obvious as the simple substitution of one known element for another in order to yield a predictable outcome where sodium phosphate dibasic is employed in place of sodium tetraborate as the basic pH modulator. Here the Promega® reference demonstrates the conventional nature of adjusting the sodium phosphate salts of phosphate buffer to generate pH values within the 5.8 to 8 range. These values include the exemplified pH values of Trollsas et al. and Jarrett et al. Further, Austin et al. illustrates that the two phosphate salts of the buffer can recapitulate the acid and basic solution pH conditions of example 10 of Jarrett et al. Thus there would have been a reasonable expectation of success for the buffer (pH modifier) substitutions. Since the composition pH, reactant concentration, and gelation time are result effective variables, they are obvious to optimize as a matter of routine experimentation. The resulting ranges for these parameters then overlap with those instantly claimed, thereby rendering the claimed ranges obvious. The inclusion of a dye as well as a mucoadhesive component, which further satisfies instant claim 15, also would follow from the teachings of Lichter et al. and Jarrett et al. as the application of the same technique to a similar product in order to yield the same improvement. A 6.8 pH 0.2M phosphate buffer produced by the combination of sodium phosphate monobasic and sodium phosphate dibasic can achieve an osmolality of about 500 mOsm/kg (as calculated by the examiner based on 3 ions/milliequivalents from the dibasic salt and 2 ions/milliequivalents from the monobasic salt). This concentration also corresponds to about a 2.6 wt% sodium phosphate solution (see instant claims 1, 18, and 21). This implies that the compositions rendered obvious with various pH values from 5.8 to 8 composed only of dye, sodium phosphate, pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate, trilysine, and water would have an overlapping range of osmolalities and sodium phosphate concentrations with those instantly claimed, thereby rendering the claimed ranges obvious (see Lichter B paragraph 101, MPEP 2144.05; instant claims 16, 20, and 25).
Regarding administration of the modified compositions, the intratympanic treatment of Meniere’s disease 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. It would then follow to employ an administration manner that permits direct visualization of the composition on the round window membrane as taught by El Kechai et al. Additionally, it would have been obvious to employ an (otic) cannula that is sized as taught by Lichter B in the modified method of El Kechai et al. to administer a volume as detailed by Lichter et al. as the simple substitution of one known component for another in order to yield a predictable outcome. It also 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 because they teach these routes as suitable for the administration of otic hydrogels. Therefore claims 1-5, 7-9, and 13-25 are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, and Austin et al. as evidenced by Alter et al.
Claims 1-5 and 7-25 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, and Austin et al. as evidenced by Alter et al.as applied to claims 1-5, 7-9, and 13-25 above, and further in view of Carfrae et al.
El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, and Austin et al. as evidenced by Alter et al. render obvious the limitations of instant claims 1-5, 7-9, and 13-25. Lichter et al. 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 claims 10-12). 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 Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, and Austin et al. as evidenced by Alter 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 1-5 and 7-25 are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, Austin et al., and Carfrae et al. as evidenced by Alter et al.
Claims 1-9 and 13-25 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, and Austin et al. as evidenced by Alter et al. as applied to claims 1-5, 7-9, and 13-25 above, and further in view of Donovan.
El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, and Austin et al. as evidenced by Alter et al. render obvious the limitations of instant claims 1-5, 7-9, and 13-25, where an otic 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. They detail visualizing the tympanic membrane with an endoscope and making an incision through which injection/instillation of the composition can occur (see paragraph 61-62 and 64-68; instant claim 6).
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 Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, and Austin et al. as a known procedure for facilitating intratympanic administration. Therefore claims 1-9 and 13-25 are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, Austin et al., and Donovan as evidenced by Alter et al.
Claims 1-25 are rejected under 35 U.S.C. 103 as being unpatentable over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, Austin et al., and Carfrae et al. as evidenced by Alter et al. as applied to claims 1-5 and 7-25 above, and further in view of Donovan.
El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, Austin et al., and Carfrae et al. as evidenced by Alter et al. render obvious the limitations of instant claims 1-5 and 7-25, where an otic 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. They detail visualizing the tympanic membrane with an endoscope and making an incision through which injection/instillation of the composition can occur (see paragraph 61-62 and 64-68; instant claim 6).
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 Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, Austin et al., and Carfrae et al. as evidenced by Alter et al. as a known procedure for facilitating intratympanic administration. Therefore claims 1-25 are obvious over El Kechai et al. in view of Jarrett et al., Lichter et al., Lichter B, Trollsas et al., the Promega® reference, Austin et al., Carfrae et al., and Donovan as evidenced by Alter et al.
Response to Arguments
Applicant's arguments filed July 31, 2026 have been fully considered. The rejections have been updated to more explicitly highlight the prior art compositions upon which they rely and their correspondence to the instantly recited composition. New and updated grounds of rejection are detailed to clarify the previous rejections and address the claim limitations as currently recited. The applicant’s arguments concerning the scope of claims 1-17 and their use of “consisting of” language are not persuasive.
As noted in the “Claim Interpretation” section above, claim 1 recites a treatment gel with open language that comprises a cross-linking polymer composition. Contrary to the applicant arguments, the fact that the cross-linking polymer composition is recited with closed language does not limit the components in the treatment gel that is administered in the claimed method. Therefore, the recited treatment gel can include the components of the cross-linking polymer composition in combination with any other component suitable for an otic application. As a result of these additional components being permitted, the treatment gel is not required to exhibit the gelation characteristics or pH of the contained cross-linking polymer composition because the additional ingredients implicitly contribute their properties to the treatment gel. Thus the composition of example 10 in Jarrett et al. which has the instantly claimed functional polymer, crosslinker, and sodium phosphate at instantly claimed proportions, along with a dye that Jarrett et al. suggest for visualization, can meet the limitations of the treatment gel of instant claim 1.
The applicant also argues that the modification of one example of Jarrett et al. based upon another of its examples is devoid of adequate motivation. This appears to be an argument that the only viable path to the combination of teachings in a prima facia case of obviousness is a teaching, suggestion, or motivation (TSM) explicitly provided by one of the source references. MPEP 2141(I) details that a reliance solely upon a TSM rationale is overly rigid and does not serve as the only route to a case of obviousness. Here, Jarret et al. teach a desired range of gelation times for their cross-linking composition. They also teach the relevant range of pH values for these compositions, the particular varieties of buffers/buffering salts to employ to achieve these pH values, the impact of an acidic pH on gelation and the desire to utilize this feature that slows gelation rate in order to attain a desired gelation time and how to compartmentalize the components in acidic and basic fractions to achieve this end. The examples are explicitly provided to illustrate how the artisan of ordinary skill could follow their guidance by highlighting particular functional polymer and crosslinker pairings of interest as well as particular pH values of interest within their taught range that can correspond to particular gelation times of interest that are also within the taught range. As detailed in MPEP 2141(II)(C), “’[a] person of ordinary skill in the art is also a person of ordinary creativity’ who ‘will be able to fit the teachings of multiple patents together like pieces of a puzzle’”. Thus a proper analysis of obviousness may account for "the inferences and creative steps that a person of ordinary skill in the art would employ”. Here the pieces at issue are within a singular document concerning a single invention that the artisan of ordinary skill would readily understand are not to be considered in isolation, but instead complement one another and support the distillation of the broader teaching Jarrett et al. into specific embodiments.
Conclusion
No claim is allowed.
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/CARALYNNE E HELM/ Examiner, Art Unit 1615
Prosecution Insights