US. Serial No. 16/908,426
`Response to Non-Final Office Action mailed January 24, 2022
`
`Attorney Docket No. 46682-701.317
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`Status of the Claims
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`REMARKS
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`Claims 31-53 are currently pending. Claims 31-33, 40-42, 45, and 49-51 are amended
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`herein. Claims 36, 38, and 46-483 were previously canceled. Support for the amendments can be
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`found atleast in the original claims and throughout the specification as filed. No new matteris
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`added.
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`Upon entry of the proposed amendments, claims 3 1-35, 37, 39-45 and 49-53 will be under
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`examination.
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`Applicant-Initiated Interview Summary
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`Applicant thanks the Examinerfor graciously granting a video conference on April 20,
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`2022, to discuss the application. Attendees included Examiner Cruz and Applicant’s counsel Tyler
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`Bird.
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`Participants discussed the outstanding rejections under 35 U.S.C. 103 in the context ofthe
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`amendments and arguments presented herein.
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`Claim Reiections - 35 U.8.C.§103
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`Claims 31-53 are rejected under 35 U.S.C. § 103 as being obvious over Morris et al. (US
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`4,952,586, heremafter “Morris” ) and in view of WoldeMussicet al. (US 5,716,952, hereinafter
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`“WoldeMussie’). Appheant respectfully disagrees for the following reasons.
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`The Office Action contends that:
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`teaches edrophonium-atropime compositions and their
`Morris et al.
`therapeutic use in medical treatments to antagonize non-depolarization blockades
`when muscle relaxationis no longer necessary(e.g. Title; Abstract; etc.) ...
`Morris does not disclose preservative,
`toxicity adjustor, and viscosity
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`agent.
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`WoildeMussie et al. teaches the use of the claimed muscarinic antagonists
`in an ophthalmic forrnulation in combination with purified water. See the abstract,
`column 2,
`lines 46-67 and column 3,
`lines 1-20 and column 4,
`lines 23-32.
`WoldeMussie teaches that the muscarinic antagonist is in the concentration of
`0.0001 to 0.1 percent weight by volume (claim 1}. The use of sodium chionde is
`taught in column 5, lines 18-22 (e.g. buffer). The use of the buffering agents, such
`as phosphate, borate and citrate is taught in column 2,
`lines 23-29. The use of
`preservatives is taught in column 5,
`lines 9-14. WoldeMussie teaches a pH
`adjustor to a pH of 4.5-7.5, a toxicity adjustor (e.g. sodium chloride, column 5,
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`US. Serial No. 16/908,426
`Response to Non-Final Office Action mailed January 24, 2022
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`Attorney Docket No. 46682-701.317
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`line 20} and a preservative in the amount of 0-0.10 (able 1).
`Non-final Office Action at pages 6 and 11.
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`To support an obviousness rejection, MPEP § 2143.03 requires “all words of a claim to be
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`considered” and MPEP § 2141.02 requires consideration ofthe “[claimed] invention andpriorart
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`asa whole.” Farther, the Board of Patent Appeal and Interferences recently confirmed that a
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`proper, post-K SR obviousness determination still requires the Office make “asearching
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`comparison of the claumed invention — including all its limitations — with the teaching of the prior
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`art.” See, dare Wada andMurphy, Appeal 2007-3733, citing fn re Ochiai, 71 F.3d 1565, 1872
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`(Fed. Cir. 1995) (emphasis in original).
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`In sum, it remains well-settled law that an obviousness
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`rejection requires at least a suggestion of all of the claim elements.
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`Amended claim 31 recites, infer alia, a kit comprising “a monotherapeutic
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`pharmaceutical composition, the monotherapeutic pharmaceutical composition comprising a sole
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`ophthalmic agent, wherein the sole ophthalmic agent is atropine or atropine sulfate.. [and] a buffer
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`to provide a pH from about 4.8to about 6.4” Apphcant submits the Office Action has not shown
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`that Morris nor WoldeMuasie, alone or combination, teach each and every element of the amended
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`claims nor has provided a reason to arrive at the present claims.
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`Morris and WoldeMussie fail to describe or provide a reason for a kit comprising a
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`manotherapentic pharmaceutical composition, the monotherapeutic pharmacentical
`composition comprising an ophthalmic agent comprising atropine or atropme sulfate
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`Morris is directed to compositions comprising both atropine and edrophonium: “[a]
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`composition is provided which includes a balanced combination ofan edrophonium component
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`and an atropine component.” See Aforris at Abstract. Nothing in Morris describes a kit
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`comprising a monotherapeutic pharmaceutical composition, the monotherapeutic pharmaceutical
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`composition comprising an ophthalmic agent such as atropine or atropine sulfate. Morris only
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`describes atropine in the context of a combined solution with edrophonium, notin a formulation in
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`which ultradiluted atropine is the monotherapeutic agent.
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`Forat least this reason, a primafacie case of obviousness has not been met.
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`Morris and WoldeMussie fal to describe or provide 4 reason {0 arrive a KH comprising a
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`pli fram ahoaut 4.8 te about 6.4
`buffer to provide a
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`US. Serial No. 16/908,426
`Response to Non-Final Office Action mailed January 24, 2022
`
`Attorney Docket No. 46682-701.317
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`Amended claim31 recites, #eralia, “a buffer to provide a pHof from about 4.8 to about
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`6.4.” Morris is silent as to this feature and WoldeMussie does not cure the deficiencies of Morris.
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`Not only does WoldeMussie not disclose atropine formulations, with regards to pH, WoldeMussie
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`merely describes a broad range of 4.5-7.5 in its general formulation Table | without any reference
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`or discussion of its importance.
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`Unexnected stability of an aqueous solution comprising a monotherancutic pharmacentical
`compasition camorisineg an ophthalmic agent comuorisime atro
`ine or atropine sulfate
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`
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`In stark contrast to the silence of WoldeMussie and Morris onstability and degradation of
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`atropine, the present applicationalso includes many stability experiments conducted on H,O-based
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`dilute atropine formulations, showing that pH and buffering agents are important parameters to the
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`stability and degradationofatropine in those formulations.
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`In particular, the various experiments on H)O-based dilute atropine formulations showthe
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`following unexpected properties at the pH specified in the pending claims:
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`® Better atropine stability
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`* Better pHstability
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`Better Atropine Stability
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`Table 244 under paragraph [00329] shows atropine sulfate purity data of different
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`formulations. AtpH of 4.8, 5.8, and 6.4, the formulations shaw goodto acceptable atropine purity
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`after 4-weeks of 25/60 storage condition. However, when the pHincreases to 6.8, the purity
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`decreases to below 95%after 4-weeks of 25/60 storage condition.
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`Table 24A. Atropine Sulfate Purity as Area-% for H,O Formulations
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`
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`Formulation3|25/60| (98.16
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`
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`
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`\4 HOpH48|40/75
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`4
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`
`
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`(98.16
`|
`25/60
`Formulation 5
`.
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`40/78
`THDOpHS 8
`(CC
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`
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`79
`05.88
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`97.54
`.
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`

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`US. Serial No. 16/908,426
`Response to Non-Final Office Action mailed January 24, 2022
`
`Attorney Docket No. 46682-701.317
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`eeOLE8094 66.83
`98.66
`Formulation 10 [25/60|
`iC MOphe4|40/75
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`Formulation 11|25/60| 99.47 97.87 96.69 |
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`
`
`
`
`
`
`
`
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`\CQ2x) H,0 pH [40/75
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`54.
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`JC HOpH68 |
`40/75
`0°C
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`Formalation 13|25/60| 97.
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`||6
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`|___43.99
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`The unexpected stability problem at higher pHis also described in paragraph [00328] of
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`the PCTapplication, stating that “At both the high and the low doses, more degradation ts
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`observed in the formulations that start ata higher pH.”
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`Better pH Stability
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`Table 18 under paragraph [00342] shows pHstability dataof different H.O-based dilute
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`atropine formulations. AtpH of 4.85, 4.98, 5.87, and 5.80, the formulations showmaintenance of
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`pHto well above4.0, even underthe more rigorous storage conditions. When pHdrops to 4.21
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`and 4.26, however, pH can slide to below4.0, a threshold often associated with eye inntation and
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`burning sensation in the eye.
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`US. Serial No. 16/908,426
`Response to Non-Final Office Action mailed January 24, 2022
`
`Attorney Docket No. 46682-701.317
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`iS iuatrs
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`D aiehihts of the atght formulations,
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`Applicant notes that without the experiments performed in the present application, one of
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`ordinary skill in the art would not recognize the problem of increased degradation occurring at pH
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`higher than 6.4 and the problem of pH sliding below4 Gat the pH lower than 4.8. As such, itis
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`Applicant whorecognizes the criticality of the pH range recited in the pending claims, and
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`confirmed it through experimentation.
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`For at least these reasons, the present claims are not obvious over Morris and
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`WoldeMussie, alone orin combination. Applicant respectfully requests withdrawal of the
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`rejection under § 103 to claim 31 and the claims dependentthereon.
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`

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`US. Serial No. 16/908,426
`Response to Non-Final Office Action mailed January 24, 2022
`
`Attorney Docket No. 46682-701.317
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`CONCLUSION
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`Applicant respectfully solicits the Examiner to expedite prosecution of this patent
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`application to issuance. Should the Examiner have any questions, the Examineris encouragedto
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`telephone the undersigned attorney at ($58) 350-2314. The Commissioner is hereby authorized to
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`charge any fees that may be required, or credit any overpayment to Deposit Account No. 23-2415,
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`referencing Atiormey Docket No. 46682-701.317,
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`Respectfully submitted,
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`WILSON SONSINI GOODRICH & ROSATI
`A Professional Corporation
`
`By:
`
`/Erin A Boyle Anderson/
`Erm A. Boyle Anderson
`Registration No. 78,136
`
`Date: April 25, 2022
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(858) 350-23 14
`Customer No. 021971
`
`-1G-
`
`