IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Application of:
`
`Mark Eller
`
`Confirmation No.:
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`2127
`
`Application No.:
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`13/872,997
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`Art Unit:
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`1629
`
`Filed:
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`April29, 2013
`
`Examiner:
`
`Gembeh, Shirley
`
`For: METHOD OF ADMINISTRATION OF Atty. Docket No.:
`GAMMA HYDROXYBUTYRATE
`WITH MONOCARBOXYLATE
`TRANSPORTERS
`
`13 314-004-999
`
`RESPONSE TO NOTICE OF NON-COMPLIANT AMENDMENT (37 CFR 1.121) AND
`
`SUPPLEMENTAL AMENDMENT AND RESPONSE UNDER 37 C.F.R. § 1.111
`
`Mail Stop AMENDMENT
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`In response to the Notice ofNon-Compliant Amendment (37 CFR 1.121) mailed
`
`November 5, 2013, and the non-final Office Action mailed September 13, 2013, and in
`
`accordance with the Rules of Practice, Applicant herein encloses a Supplemental Amendment
`
`and Response.
`
`Amendments to the Claims begin on page 2 of this paper.
`
`Remarks begin on page 8 of this paper.
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`SVI-135355vl
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`Ranbaxy Ex. 1027
`IPR Petition - USP 8, 772,306
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
`U.S. Patent Application No. 13/872,997
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`AMENDMENTS TO THE CLAIMS
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`This listing of the claims will replace all prior versions, and listings, of claims in the
`
`application.
`
`Listing of claims:
`
`1.
`
`(Currently Amended) A method for treating a patient who is suffering from excessive
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`daytime sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy, sleep time disturbances,
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`hypnagogic hallucinations, sleep arousal, insomnia, or nocturnal myoclonus with gamma(cid:173)
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`hydroxybutyrate (GHB) or a salt thereof, said method comprising:
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`orally administering to the patient in need of treatment an [[adjusted]] effective
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`dosage amount of the GHB or salt thereof when the patient is receiving a concomitant
`
`administration of valproate.
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`2.
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`(Currently Amended) The method in accordance with claim 1, wherein the [[adjusted]]
`
`effective dosage amount is reduced by at least about a 15% reduction of the dose of the
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`GHB or salt thereof normally given to the patient.
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`3.
`
`(Currently Amended) The method in accordance with claim 1, wherein the [[adjusted]]
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`effective dosage amount is reduced bet\veen the range a reduction of about 1% to 5%,
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`about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25%
`
`to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, or about 45% to 50%,
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`relative to the dose of the GHB or salt thereof normally given to the patient.
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`4.
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`(Currently Amended) The method in accordance with claim 1, wherein the GHB salt is
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`administered at a normal dose ofbetween 1 gram and 10 grams per day.
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`5.
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`(Original) The method in accordance with claim 1, wherein the patient is suffering from
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`narcolepsy.
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
`U.S. Patent Application No. 13/872,997
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`6.
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`(Original) The method in accordance with claim 1, further comprising administering
`
`aspirin to the patient.
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`7.
`
`(Currently Amended) A method of safely administering GHB or a salt thereof for
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`excessive daytime sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy, sleep time
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`disturbances, hypnagogic hallucinations, sleep arousal, insomnia, or nocturnal myoclonus
`
`in a human patient, said method comprising:
`
`determining if the patient has taken, or will take, a concomitant dose of valproate;
`
`and
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`orally administering a reduced amount of the GHB or salt thereof to the patient
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`compared to a normal dose ofbetween 1 and 10 grams per day so as to diminish the
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`additive effeets ofthe GHB or salt iliereof\vhen administered 'tvith val)9roate.
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`8.
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`(Original) The method in accordance with claim 7, wherein the amount ofGHB or salt
`
`thereof is reduced at least 10% to 30% of the normal dose for the patient.
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`9.
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`(Original) The method in accordance with claim 7, wherein the amount ofGHB or salt
`
`thereof is reduced at least 15% of the normal dose for the patient.
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`10.
`
`(Cancelled).
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`11.
`
`(Original) The method in accordance with claim 7, herein the valproate is administered
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`within two weeks of administration of the GHB or salt thereof.
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`12.
`
`(Original) The method in accordance with claim 7, wherein the valproate is administered
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`within three days of administration of the GHB or salt thereof.
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`13.
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`(Original) The method in accordance with claim 7, wherein the patient is suffering from
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`narcolepsy.
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
`U.S. Patent Application No. 13/872,997
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`14.
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`(Original) The method in accordance with claim 7, further comprising administering
`
`aspirin to the patient.
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`15.
`
`(Currently Amended) A method for treating a patient who is suffering from narcolepsy,
`
`said method comprising:
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`administering a therapeutically effective amount of a formulation containing a
`
`GHB salt to a patient starting at a concentration ofbetween 350 and 750 mg/ml [[and]]
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`with a pH ofbetween 6 and 10, said formulation being administered in two doses before
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`bed and 1 to 2 hours thereafter;
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`determining if the patient is also being administered valproate;
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`warning of a potential drug/drug interaction due to the combination ofvalproate
`
`and the GHB salt; and
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`recommending reducing the dose of the GHB salt at least 15% to compensate for
`
`the effect caused by valproate.
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`16.
`
`(Original) The method in accordance with claim 15, wherein the valproate is
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`administered within two weeks of administration of the GHB salt.
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`17.
`
`(Original) The method in accordance with claim 15, wherein the valproate is
`
`administered within three days of administration of the GHB salt.
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`18.
`
`(Original) The method in accordance with claim 15, wherein the GHB salt is
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`administered starting at a concentration of between 450 to 550 mg/ml.
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`19.
`
`(Original) The method in accordance with claim 15, wherein the GHB formulation has a
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`pH between 6.5 and 8.
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`20.
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`(Original) The method in accordance with claim 15, further comprising administering
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`the reduced dose of the GHB salt to the patient.
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
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`21.
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`(Original) The method in accordance with claim 15, wherein the GHB salt comprises a
`
`single or a mixture of salts of GHB selected from the group consisting of a sodium salt of
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`hydroxybutyrate (Na•GHB), a potassium salt of gamma-hydroxybutyrate (K•GHB), a
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`magnesium salt of gamma-hydroxybutyrate (Mg•(GHB)2), and a calcium salt of gamma(cid:173)
`
`hydroxybutyrate (Ca•(GHB)2).
`
`22.
`
`(Original) The method in accordance with claim 15, further comprising administering
`
`aspirin to the patient.
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`23.
`
`(Currently Amended) The method in accordance with claim 1, wherein the [[adjusted]]
`
`effective dosage amount is reduced from 4.5 to 9 grams per day relative to the dosage
`
`a-J9)9rov:ed by the PDl., for treatmeH-1:.
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`24.
`
`(Currently Amended) The method in accordance with claim 2, wherein the dose
`
`normally given to the patient is from 4.5 to 9 grams per day the dosage a)9)9FOv:ed by the
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`PDl., for treatmeH-1:.
`
`25.
`
`(Currently Amended) The method in accordance with claim 4, wherein the normal dose
`
`is from 4.5 to 9 grams per day the dosage a)9)9FOv:ed by the PDA for treatmeH-1:.
`
`26.
`
`(Currently Amended) The method in accordance with claim 1, wherein the [[adjusted]]
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`effective dosage amount is between 3 grams and 7 grams per day.
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`27.
`
`(Currently Amended) The method in accordance with claim 1, wherein the [[adjusted]]
`
`effective dosage amount is between 3.5 grams and 4 grams per day.
`
`28.
`
`(New) A method for treating a patient who is suffering from narcolepsy, said method
`
`compnsmg:
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`administering a therapeutically effective amount of a formulation containing a
`
`GHB salt to a patient;
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`determining if the patient is also being administered valproate;
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
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`recommending a 20% decrease in the starting dose of GHB such that a patient
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`starts taking GHB at an adjusted dosage amount between 3.5 grams and 4 grams GHB
`
`per night administered orally in two doses.
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`29.
`
`(New) The method in accordance with claim 28, wherein the starting adjusted dosage
`
`amount is about 3.6 grams.
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`30.
`
`(New) A method for treating a patient who is suffering from narcolepsy, said method
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`compnsmg:
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`orally administering a therapeutically effective amount of a formulation
`
`containing a GHB salt in two doses;
`
`determining if the patient is also being administered valproate;
`
`recommending a 20% decrease in the starting dose of GHB such that the amount
`
`that the patient is administered is reduced to about 3.6 grams GHB per day.
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`31.
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`(New) The method in accordance with claim 7, further comprising recommending to
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`decrease the starting dose by 20%.
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`32. [[34.]] (New) The method in accordance with claim 15, comprising recommending
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`reducing a starting dose at least 20%.
`
`33. [[35.]] (New) The method in accordance with claim 15, further comprising adding water to
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`the formulation.
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`34. [[36.]]
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`(New) The method in accordance with claim 18, further comprising adding water to
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`the formulation.
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`35. [[37.]] (New) The method in accordance with claim 28, further comprising optionally
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`diluting the formulation from a starting concentration of between 350 and 750 mg/ml
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`with a pH ofbetween 6 and 10.
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
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`36. [[38.]] (New) The method in accordance with claim 30, further comprising optionally
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`diluting the formulation from a starting concentration of between 350 and 750 mg/ml
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`with a pH ofbetween 6 and 10.
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
`U.S. Patent Application No. 13/872,997
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`REMARKS
`
`Claims 1-27 are pending in the above-identified application. Claims 1-4, 7, 15 and 23-27
`
`are amended for purpose of clarity, and claim 10 is cancelled. Claims 28-38 are newly added in
`
`the Response to Office Action dated October 31,2013. Application herein amends claim
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`numbering for claims 32-36, correcting a typographic error. With this Supplemental
`
`Amendment, claims 28-36 are the newly added claims. Support for the new claims is found in
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`the existing claims and in paragraph [0149] of the specification for the dose amounts, and
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`decreases in doses (for example, the starting dose in claims 29 and 30 was determined by
`
`reducing the starting dose of 4.5 by 20%). Support for the amendments to claims 23-25 is found
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`in paragraph [0149] of the specification.
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`Claims 1, 4-5, 7, 10 and 13 are rejected under pre-AlA 35 U.S.C. § 103(a) over Johnson
`
`(US 2008/0293698) in view ofCivelli et al. (US 2003/0171270). Claims 1, 4-7, 10 and 13-14
`
`are rejected under pre-AlA 35 U.S.C. § 103(a) over Johnson in view ofCivelli et al., and further
`
`in view of Dalton et al. (US 2001/02376664).
`
`Claims 1-27 are provisionally rejected under the judicially created doctrine of
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`obviousness-type double patenting as being unpatentable over claims 1-18 ofU.S. Patent
`
`Application No. 13/873,000, in view of Johnson. Claims 1-27 are also provisionally rejected
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`under the judicially created doctrine of obviousness-type double patenting as being unpatentable
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`over claims 3-15 and 93-96 ofU.S. Patent Application No. 13/873,714, in view of Johnson.
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`RECORD OF INTERVIEW
`
`Applicant wishes to thank Examiner Gembeh for participating in the interview dated
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`October 22, 2013 with the present inventor Dr. Mark Eller and representative Mr. Philip
`
`McGarrigle. The Examiner had many helpful language suggestions that have been incorporated
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`into the present amendments. No agreement was reached regarding the claims.
`
`The Rejections
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`DISCUSSION
`
`The Examiner states that "Johnson teaches treating patients with acquired resistance to
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`GABAnergic (ARG) agents" but does "not teach that the patient is concomitantly being
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
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`administered valproate." (See page 5 of the Office Action (OA).) The Examiner also states that
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`"Johnson teaches that the treatment of ARG can be combined with other agents (see 0275-278)."
`
`(See page 5 of the OA.)
`
`The Examiner further states that "Civelli et al. teach treating sleep disorders such as sleep
`
`apnea, daytime sleepiness, narcolepsy (see 0106 as required by claims 1 and 4) wherein these
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`absence seizures respond[s] to valproate (see 043) and gamma-hydroxybutyrate (see 048)." (See
`
`page 4 of the OA.) The Examiner further states that "[a]lthough Johnson and Civelli did not
`
`exactly teach determining if the patient took the concomitantly (as required by instant claim 7), it
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`would have been obvious to one of ordinary skill in the art to have questioned the patient treated
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`if they took their medication." (See page 4 of the OA.)
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`Johnson (US 2008/0293698)
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`Johnson is directed to methods and compositions for treating acquired resistance to
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`GABAminergic agents (ARG). ARG consists of types I and II, which include the conditions
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`described at, for example, paragraphs [0028]- [0032] and [0191] of this reference. Johnson
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`provides a very general disclosure suggesting that ARG may be treated with agents in as many as
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`eight classes (classes I-VI) plus vitamins (see Johnson at paragraphs [0053], [0283]- [0285]) and
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`opioids (see paragraph [0220]). However, Johnson provides few details about the effects of
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`different combinations of agents. As the Examiner acknowledges, Johnson does not teach
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`concommitant administration with valproate. Further, Johnson does not teach or suggest that
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`val pro ate could be combined with GHB, or what might be the effects of the two if combined.
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`Civelli et al. (US 2003/0171270)
`
`Civelli et al. disclose therapeutic compositions and methods relating to prolactin
`
`releasing peptide (PrRP). Civelli et al. also disclose that valproate can treat absence seizures and
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`can be administered together with PrRP (see paragraph [0043] and the claims). Civelli et al.
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`further disclose that PrRP is used for treating absence seizures and also ailments such as sleep
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`disorders (see paragraph [0105]). Civelli et al. do not teach or suggest that valproate could be
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`combined with GHB or any of the effects of the combination.
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
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`Johnson and Civelli et al. Cannot be Combined
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`Applicant respectfully suggests that Civelli et al. do not suggest the combination of GHB
`
`and valproate as this reference actually teaches against the presently claimed combination. For
`
`example, Civelli et al. disclose that valproate is used to treat absence seizures (see paragraph
`
`[0043]), and GHB is used in induce them; these are two opposite effects.
`
`See, for example, paragraph [0048] of Civelli et al., which discloses:
`
`Other relevant mammalian models of absence seizures in humans include
`pharmacological models, in which absence seizures are induced in laboratory
`animals, such as rodents, cats and primates, by administration of
`pentylenetetrazol, penicillin, gamma-hydroxybutyrate or GABA agonists (for a
`review, see Snead, Epilepsia 29:361-368 (1988)). Additionally, absence seizures
`can be induced in primates by thalamic stimulation (see, for example, David et al.,
`J Pharmacal. Methods, 7:219-229 (1982)).
`
`Consequently, one of ordinary skill in the art would not have combined valproate and
`
`GHB based on Civelli et al. The intent of the val pro ate and GHB in the present application is
`
`that both compounds would be used for therapeutic purposes, but Civelli et al. teach that GHB
`
`can create a therapeutic problem using GHB. Accordingly, Applications respectfully request that
`
`the Examiner reconsider and withdraw the rejection of claims 1, 4-5, 7, 10 and 13 under pre-AlA
`
`35 U.S.C. § 103(a) over Johnson, in view ofCivelli et al.
`
`The References Do not Show The Unexpected Effect ofValproate on GHB
`
`The above discussion shows that Johnson and Civelli et al. are not combinable, but even
`
`if these references were combined, they would not teach or suggest that there would be a change
`
`in the GHB in vivo effect caused by valproate. Furthermore, it would not have been known prior
`
`to the present application what that effect would be, such as an increase or decrease in the in vivo
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`effect of GHB. For example, valproate could have created an impact through its activity as an
`
`MCT inhibitor, or by another mechanism, such as inhibiting the enzyme GHB dehydrogenase.
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`For example, ifvalproate predominantly worked as an MCT inhibitor, then one would have had
`
`to increase the dose of GHB to maintain the effective concentration in the blood. If the effect of
`
`valproate was on GHB dehydrogenase, then one would have had to decrease the GHB dose.
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`These two effects are opposite to one another and could not have been predicted prior to the
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`disclosure of the present invention. Accordingly, for this additional reason, Applications
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
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`respectfully request that the Examiner reconsider and withdraw the rejection of claims 1, 4-5, 7,
`
`10 and 13 under pre-AlA 35 U.S.C. § 103(a) over Johnson, in view ofCivelli et al.
`
`Dalton does not Cure the Defects of Johnson and Civelli et al.
`
`The Examiner cites Dalton et al. for teaching "administering aspirin (0238) [and]
`
`gamma-hydroxybutryate (see 0251) in the treatment of narcolepsy (see 0500)". (See page 6 of
`
`the OA).
`
`Indeed, Dalton et al. discloses at paragraph [0002] as follows:
`
`This invention provides SARM compounds and uses thereof in treating
`and preventing muscle wasting in patients with non-small cell lung cancer
`(NSCLC); treating pre-cachexia or early cachexia (preventing muscle wasting in a
`cancer patient); treating and preventing loss of physical function due to cancer or
`cancer therapy; and increasing physical function or survival.
`
`However, Dalton et al. does not cure the defects of Johnson and Civelli et al.
`
`As discussed above, Johnson and Civelli et al. should not be combined, and even if
`
`combined would not render the present claims obvious. The addition of Dalton does not make
`
`up for the lack of disclosure in either Johnson or Civelli et al. Applicants also assert that Dalton
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`does not show or suggest the features of the present claims which require that the GHB dose be
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`adjusted upon concomitant administration of valproate.
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`Accordingly, Applications respectfully request that the Examiner reconsider and
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`withdraw the rejection of claims 1, 4-7, 10 and 13-14 under pre-AlA 35 U.S.C. § 103(a) over
`
`Johnson, in view of Civelli et al. and Dalton et al.
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`Obviousness Type Double Patenting Rejections
`
`Applicants acknowledge that present claims 1-27 are provisionally rejected under the
`
`judicially created doctrine of obviousness-type double patenting as being unpatentable over
`
`either claims 1-18 of U.S. Patent Application No. 13/873,000, or claims 3-15 and 93-96 ofU.S.
`
`Patent Application No. 13/873,714, in view of Johnson.
`
`Applicants respectfully request that the Examiner hold these rejections in abeyance until
`
`all other rejections and objections are overcome. At that time, Applicants note that, pursuant to
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`MPEP § 804, if a provisional nonstatutory obviousness-type double patenting rejection is the
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`only rejection remaining in the earlier filed of two pending applications, while the later-filed
`
`application is rejectable on other grounds, the Examiner should withdraw the rejection and
`
`permit the earlier-filed application to issue as a patent. Pursuant to the same section, if
`
`provisional nonstatutory obviousness-type double patenting rejections in the two applications are
`
`the only rejections remaining in those applications, the Examiner should withdraw the
`
`nonstatutory obviousness-type double patenting rejection in the earlier filed application thereby
`
`permitting that application to issue. Also pursuant to the same section, ifboth applications are
`
`filed on the same day, the Examiner should determine which application claims the base
`
`invention and which application claims the improvement (added limitations), and withdrawn the
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`nonstatutory obviousness-type double patenting rejection in the base application.
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`SUPPLEMENTAL AMENDMENT AND RESPONSE
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`CONCLUSION
`
`Applicants submit that the supplemental amendments to the claims are to correct
`
`inadvertent typographical errors, and are fully supported by the specification as originally filed
`
`and present no new matter. Entry thereof is respectfully requested.
`
`As stated above, Applicants believe that the amended claims are allowable as the cited
`
`references do not teach or suggest the amended claims. They respectfully request that the
`
`Examiner reconsider and withdraw the rejections and pass the claims to issuance.
`
`No fee is believed to be due in connection with the filing of the present Supplemental
`
`Amendment and Response. However, the Commissioner is hereby authorized to charge any
`
`required fee to Jones Day Deposit Account No. 50-3013 (order no. 923865-999004).
`
`Date: November 13, 2013
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`Respectfully submitted,
`
`/A. Patricia Campbell/
`67, 116
`A. Patricia Campbell
`(Reg. No.)
`For: Anthony M. Insogna (Reg. No. 35,203)
`JONES DAY
`222 East 41st Street
`New York, New York 10017-6702
`(212) 326-3939
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