Docket No. 4000.3010 US3
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Appellants:
`
`Elliot Ehrich
`
`13/871,534
`Application No.:
`April26, 2013
`Filed:
`Confirmation No.: 5842
`For:
`NALTREXONE LONG ACTING FORMULATIONS AND
`METHODS OF USE
`
`Group No.: 1627
`Examiner: Carter, Kendra D.
`
`APPEAL BRIEF
`
`Mail Stop Appeal Briefs Patents
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`This Brief is being filed pursuant to 37 CFR §41.37. The required sections (i-v)
`under 37 CFR §41.37(c)(1) are set forth below under separate headings.
`
`(i)
`
`The Real Party In Interest
`The real party of interest in this appeal is the assignee, Alkermes Pharma Ireland
`Limited by virtue of the assignment recorded on October 16, 2015 at Reel 036809 and
`Frame 0447.
`
`(ii)
`
`Related Appeals, Interferences, and Trials
`There are no related appeals, interferences, or trials at this time known to the
`Appellant, the assignee or its representative which will directly affect or be directly
`affected by or have a bearing in the Board's decision in the pending appeal.
`
`(iii)
`
`Summary of Claimed Subject Matter
`Independent claim 1 recites a method for treating an individual in need of
`naltrexone comprising the step of administering by intramuscular injection a long acting
`formulation comprising naltrexone to the individual wherein the serum AUC of
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`APOTEX EXHIBIT 1021
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`Application No. 13/871,534
`
`naltrexone is at least about two times greater than that achieved by 50 mg/day oral
`administration, wherein the long acting formulation of naltrexone is administered only
`once during at least a two week period, and comprises between 160 and 240 mg of
`naltrexone or about 310 to about 480 mg of naltrexone. Support for claim 1 is found on
`page 3, lines 7-11 and 29-31; page 4, line 1; page 6, lines 3-6 and 24-31; and page 7, line
`1.
`
`Claim 6 depends directly from claim 1 and further recites that the long acting
`formulation releases naltrexone for a period of about four weeks. Support for claim 6 is
`found on page 6, lines 24-25.
`Claim 7 depends directly from claim 1 and further recites that the long acting
`formulation is administered in a dose of about 380 mg of naltrexone. Support for claim 7
`is found on page 4, lines 1-2.
`Claim 11 depends directly from claim 1 and further recites that the long acting
`formulation is administered over a period of about 24 weeks or longer. Support for claim
`11 is found on page 2, lines 19-22.
`Claim 14 depends directly from claim 1 and further recites that the individual is
`an individual afflicted by alcohol dependency. Support for claim 14 can be found on page
`7, lines 21-24.
`Claims 16-17 depend directly from claim 1 and further recite that the long acting
`formulation comprises a polylactide polymer, a poly lactic acid polymer, or a polylactide-
`co-glycolide polymer. Support for claims 16 and 17 can be found on page 4, lines 10-12.
`Claim 18 depends directly from claim 1 and further recites that the naltrexone is
`present in the long acting formulation at a concentration of about 35% by weight.
`Support for claim 18 can be found on page 5, lines 24-27.
`Claim 22 depends directly from claim 11, which depends directly from claim 1,
`and further recites that the method of claim 11 further comprises a second administration
`of the long acting formulation comprising naltrexone at least about 28 days after the first
`administration. Support for claim 22 can be found on page 7, lines 5-8.
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`Application No. 13/871,534
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`(iv) Argument
`A.
`Claims 1, 6, 7, 11, 14, 16-18, and 22 are rejected under pre-AlA 35 U.S.C.
`103(a) as being unpatentable over Heinala et al. (Journal of Clinical
`Psychopharmacology, 2001, vol. 21, pp. 287-292) as applied in claim 1 in view of
`Bartus et al. (Neuropsychopharmacology, 2003, vol. 28, pp. 1973-1982), Leavitt
`(Addiction Treatment Forum Ed., 2002, pp. 1-8), and Johnson (Therapeutics and
`Clinical Risk Management, 2007, vol. 3, no. 5, pp. 741-749).
`
`Claim 1
`The Examiner asserts that one of ordinary skill in the art at the time of the
`invention would have found it obvious and been motivated to modify the method of
`Heinala et al. and the claimed amounts of naltrexone administered according to the
`teachings of the secondary references. [Final Office Action dated March 17, 2015, page
`7, first paragraph, through page 8; Upheld in Advisory Action dated August 4, 2015,
`page 2, first paragraph]
`The Examiner continues on page 8 of the Final Action, asserting it is considered
`obvious that "once one administers the formulation and method of Heinala et al. in view
`of Bartus et al. and Leavitt, one would obviously obtain the pharmacokinetics claimed."
`Appellant respectfully disagrees.
`Many of the facts related to this appeal are not in dispute.
`
`1. Heinala does not teach long acting naltrexone formulations, intramuscular
`administration, or the pharmacokinetic profile
`Heinala is relied upon to show that oral naltrexone (50 mg/day) can be used to
`treat alcohol dependence in non-abstinent alcoholics.
`It is admitted that Heinala does not teach ( 1) administration of a long acting form
`of naltrexone (2) to achieve a pharmacokinetic profile of at least 2 times the oral dosage
`(as measured by the serum AUC) (3) by injection ( 4) on at least a biweekly or monthly
`schedule ( 5) over a period of 24 weeks or more of ( 6) formulations that comprise a
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`Application No. 13/871,534
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`polylactide or PLGA. Thus, it appears to be admitted that Heinala does not teach any
`material limitation of the claim (the formulation, mode of administration, dosing
`regimen, dose or pharmacokinetic profile).
`The Examiner does not dispute that Heinala also teaches oral administration of
`naltrexone on an as needed basis when the craving for alcohol is high (see the last 4 lines
`of the article) and that Heinala warns against the possibility that long term naltrexone use
`may produce supersensitivity of the opioid receptors and other side effects. Thus, the
`fact that Heinala also has teachings away from the claimed invention also does not appear
`to be in dispute.
`The Examiner then relies upon three secondary references to teach these missing
`limitations in an effort to arrive at the claimed invention.
`
`2. Leavitt does not teach long acting injections
`Leavitt is relied upon to teach that naltrexone can be orally administered at doses
`ranging from 12.5 mg/day to 150 mg/day. Leavitt is a review article of several clinical
`trials of orally administered naltrexone. The Abstract suggests flexible dosing and, like
`Heinala, on an "as needed basis."
`Leavitt does not teach that intramuscular injection of a 380 mg long acting
`formulation can achieve a serum AUC of twice 50 mg/day oral dosing. Nor does Leavitt
`teach that such a dose by injection (either 380 mg, for example, or twice the AUC of oral
`naltrexone) is desirable. In fact, since a long acting formulation would not be "flexible
`dosing" on an "as needed basis," it does not appear to be disputed that Leavitt, like
`Heinala, provide teachings away from the claimed invention.
`
`3. Bartus does not teach the desired dosing or a method of manufacture
`Bartus is relied upon to show a long acting formulation comprising PLGA and
`about 35% naltrexone, called Vivitrex® microspheres. Bartus administered 50 mg/kg of
`the microspheres to Sprague Dawley rats and repeated the dose after 34 days to a group
`of these rats.
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`Application No. 13/871,534
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`It is not disputed that Bartus does not teach (1) that it is desirable to administer
`naltrexone to achieve an AUC that is at least twice that of the 50 mg/day oral dose in
`humans, (2) the human dose in mg ofnaltrexone, (3) how one would select a human dose
`from the rat dose, or (3) a method for manufacturing Vivitrex® microspheres.
`Therefore, it is not disputed that Bartus does not teach the missing limitations of
`the claims relating to the human dose and pharmacokinetic profile or a method of
`manufacturing the product.
`
`Johnson is not prior art and does not teach how to make the product
`4.
`Johnson was published in 2007. The effective filing date for the present claims is
`2004. It is not in dispute that Johnson is not available as prior art.
`In spite of this fact, the Examiner states that Johnson is "an evidentiary art to
`prove what is in VIVITREX." [Advisory Action, Page 5] and that Vivitrex® is
`naltrexone formulated into poly-(lactide-co-glycolide) micro spheres. [Final Action, page
`11, first paragraph]. It appears that the Examiner admits that Bartus does not teach what
`is in Vivitrex® microspheres and that one must resort to literature that is not prior art.
`Johnson is not relied upon, and cannot be relied upon, to provide a teaching of the
`state of the art at the time of the invention. Additionally, while Johnson does state that
`Vivitrex® microspheres contain PLGA and naltrexone, like Bartus, Johnson also does
`not provide a teaching of how to make Vivitrex® microspheres.
`
`5. 2003 Alkermes Press Release is improperly cited, is not prior art and does not
`teach how to make the product
`In the Advisory Action dated August 4, 2015, the Examiner asserts that the
`Alkermes Press Release of December 8, 2003 teaches a 380 mg naltrexone injectable
`suspension with the poly-lactide co-glycolide polymer can be administered once a month
`to humans. [Advisory Action, page 2, third paragraph; page 5, lines 1-4; page 8, last
`seven lines].
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`Application No. 13/871,534
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`Firstly, it is not clear if the Examiner is relying upon the Press Release in the
`rejection as it does not appear in the statement of the rejection. If the Press Release is
`being relied upon, the rejection is a new ground of rejection and maintaining finality was
`improper. Appellant has a right to rebut the newly relied upon reference. MPEP Sec.
`706.07(e) and 1207.03.
`Secondly, the Press Release is obviously derived from Appellant's invention (as
`evidenced by Evidence Documents #1, #2, and #4 -7). The instant application has a
`priority date of April22, 2004. While Appellant has not been afforded the opportunity to
`present a Declaration by Inventor Ehrich explicitly addressing the point (e.g., under 3 7
`CFR 1.131 or a so-called Katz declaration under 35 USC 1.132), it is apparent on the
`face of the underlying facts. Thus, this reference is not available as prior art as it is not a
`publication by others.
`Thirdly, while the Press Release describes a 380 mg dose ofVivitrex
`microspheres, it is silent as to (1) how to make the microspheres and (2) the claimed
`serum AUC of at least 2 times that of oral naltrexone at 50 mg/day.
`
`6. The pharmacokinetic profile of a drug product is dependent on the dose and
`formulation
`It is not disputed that the pharmacokinetic profile of a 380 mg. dose ofVivitrex®
`microspheres is different than the pharmacokinetic profile of a 190 mg. dose of
`Vivitrex® microspheres when administered to humans. (Evidence Document 1; Pages 1-
`2).
`
`It Is not disputed that the pharmacokinetic profile of a 380 mg. dose ofVivitrex®
`microspheres is different than the pharmacokinetic profile of a dose of naltrexone long
`acting microspheres made with PLA as disclosed by US Patent 6,306,425 to Tice et al.
`(Evidence Document 4; Pages 2-3 and Evidence Document 8). The Examiner concedes
`this fact in the Advisory Action, Page 10.
`Therefore, it is not in dispute that the pharmacokinetic profile of naltrexone long
`acting microspheres is dependent on the dose and formulation and is simply not inherent
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`Application No. 13/871,534
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`to any dose of any PLGA microsphere containing naltrexone.
`The Examiner appears to ignore the fact that the result (superior efficacy and
`pharmacokinetic profile) is dose dependent and Bartus does not teach a human dose.
`That is, the administration of Bartus' microspheres will not inherently achieve the
`claimed pharmacokinetic result (a serum AUC at least two times the 50 mg/day oral
`dose) at all doses. One must choose the dose to achieve efficacy and the pharmacokinetic
`result. It is clear error for the Examiner to supply what is missing from Bartus (e.g., the
`human dose and pharmacokinetic profile) with Johnson (which is not prior art) to dismiss
`the evidence of unexpected results as inherent in the microspheres.
`
`7. No prior art reference teaches the claimed dose or suggests selecting the
`pharmacokinetic profile
`A close review of each of the prior art references relied upon in the statement of
`the rejection (Heinala, Leavitt, and Bartus) establishes that none disclose the
`administration of a long acting formulation having 160 to 240 mg or 310 to 480 mg
`naltrexone to an individual to achieve a serum AUC of at least 2 times that of oral
`naltrexone at 50 mg/day.
`Heinala teaches oral dosing at 50 mg/day daily and, after several weeks, as
`needed when alcohol craving is high. Leavitt (a review of oral clinical trials) appears to
`echo the teachings of Heinala that efficacy can be achieved by oral dosing on an as
`needed basis. These teachings advocate for less than a 50 mg/day oral dose after several
`weeks and that daily dosing is unnecessary. These teachings advocate against
`administering a long acting formulation because a long acting formulation cannot achieve
`a dosing "as needed," much less an injection that achieves serum plasma levels at least
`twice the oral dose.
`Bartus advocates for long acting formulations. However, this article does not
`promote dosing to achieve serum AUCs of at least twice the approved oral dosing.
`While Johnson teaches the dosing for Vivitrex® microspheres at 380-400 mg and
`reports favorable pharmacokinetic results (albeit the serum AUC is not disclosed), the
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`Application No. 13/871,534
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`article is not prior art and is, with respect to Vivitrex®, clearly derived from the
`Appellant's own work.
`No reference teaches how to make a naltrexone long acting formulation that will
`achieve the pharmacokinetic profile as claimed at the claimed doses. No reference
`teaches that it would be desirable to do so.
`
`8. The CDER establishes that the human dose is not a simple extrapolation from
`the rat dose of Bartus
`In the Final Office Action, the Examiner relied upon the CDER Guidance for
`Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for
`Therapeutics in Adult Healthy Volunteers, July 2005, pp. 1-7 (the "CDER") to
`extrapolate a rat dose to a human dose (attached hereto as Evidence Document #3). She
`maintains that she is continuing to rely on the CDER in the Advisory Action, not as a
`reference in the rejection, but rather as evidence that it is within the skill of the art to
`determine dosages based on animal studies. [Final Action, page 10, last paragraph
`through page 11; Advisory Action, page 7, middle of last paragraph; Advisory Action
`page 8, 10 lines from bottom of page]
`Appellant asserts that the Examiner is, in fact, relying on the document for
`evidence and that the rejection is improperly stated. In addition, it does not provide the
`requisite teaching as detailed below.
`In the Final Office action, the Examiner made certain mathematical calculations
`in an attempt to show that the claimed dose was an obvious extrapolation from Bartus'
`rat dose. Appellant challenged the factual bases for the allegations made in the Final
`Rejection. The Examiner admits in the Advisory Action that her calculations found on
`page 10 of the Final Action are incorrect.
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`Application No. 13/871,534
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`The Examiner asserted the claimed amounts ofnaltrexone for human injection are
`obvious to determine.
`For instance, the conversion of [a] mouse (i.e. rat) to human mg/kg
`dosages according to the CDER (Guidance for Industry Estimating the
`Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in
`Adult Healthy Volunteers, July 2005, pp. 1-7) is to multiply the animal
`dose by 0.08 (see page 7, Table 1)." [Final Action of March 17, 2015,
`page 10, last paragraph]
`
`Appellants established, to the Examiner's satisfaction, that this was factually
`incorrect.
`
`a. The Examiner's calculations were incorrect
`The Examiner's statement relied upon mistaken factual assumptions.
`Mice are not rats.
`1.
`The Examiner states the conversion of a "mouse (i.e. rat) to human mg/kg
`dosages ... is to multiply the animal dose by 0.08." A rat is not a mouse (as evidenced by
`the fact that the two animals are listed separately in the Table) and the conversion factors
`differ. Table 1 lists the rat conversion factor as being twice that of the mouse conversion
`factor. Thus, contrary to the Examiner's statement, Table 1 on page 7 of CDER guidance
`teaches 0.16 as a conversion factor for rat-to-human, not 0.08.
`In fact, Appendix B of the CDER makes clear that the "rat," in this instance, is a
`small rat and the conversion is not linear based on weight. Appendix B states that the km
`(the inverse of the conversion factor) of a 100 gratis 5.2 (conversion factor is 0.19) and
`7.0 for a 150 g rat (conversion factor is 0.16) listed in Table 3. Bartus, on the other hand,
`used Sprague Dawley rats weighing 450 g, more similar to the guinea pig weight ( 400 g)
`listed in Table 3, with a conversion factor of0.216. If one were to use the guinea pig
`conversion, the 50 mg/kg of a 400 g animal dose is 10.8 mg/kg or 648 mg for a 60 kg
`human.
`Thus, if one were to assume that these conversion factors can be applied to depot
`formulations of naltrexone and that Bartus' rat dose was appropriate to extrapolate to a
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`Application No. 13/871,534
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`human dose, a 50 mg/kg rat dose would convert to 8 mg/kg in a human or 480 mg for the
`assumed 60 kg human (see Footnote a), and not 4 mg/kg as asserted by the Examiner.
`The Examiner's factual mistake that the claimed dose is a simple extrapolation of
`Bartus's rat dose to a human dose is clearly erroneous because a mouse is not a rat.
`
`n.
`
`Humans are assumed to be 60 kg, not a range of weights assumed
`by the Examiner
`Additionally, the Examiner asserted that the "HED" should be arithmetically
`applied across an apparently arbitrary range of"120 pounds (54.5 kg) to 250 pounds
`(113.6 kg)" by multiplying each human weight by the conversion factor (e.g., 4 for
`mouse or 8 for rat or 10.8 for a 400 g. animal). That was also factually incorrect.
`The CDER states that the conversion rates in Table 1 on page 7 assume a 60 kg
`human, not a range of weights. See Footnote a. It is typical for clinical trials and
`approved drugs to use standard doses for patients and to not arithmetically "titrate" the
`dose by each patient's weight. There is no factual basis for the Examiner to assert that the
`CDER suggests the maximum safe starting dose is actually a range of doses calculated
`for 120 to 250 pound adult healthy volunteers. It is an undisputed fact that the approved
`oral dose of naltrexone is 50 mg/day, irrespective of moderate variabilities in the weights
`of the adults. The mean weight for the adults dosed with the formula of the claims in the
`clinical trial as described in the specification were about 84 kg (overall), 90 kg for males
`and 71 kg for females. Again, the dose was not "titrated" to each patient's weight. Thus,
`the Examiner's decision to do so (compounded with selecting the wrong animal for
`conversion), resulting in an artificial range overlapping with the claimed dose was
`incorrect.
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`The Correct Formula was not used
`111.
`Even assuming the Examiner was correct1 that the CDER teaches a range of
`starting doses designed by a weight range of human adults, the formula the Examiner
`used was incorrect for establishing that range. The Examiner's formula assumed the
`HED is the product of the animal dose and a simple ratio of animal weight to human
`weight. In contrast, the CDER states in Footnote a, that if one were to deviate from the
`assumption of a 60 kg human, the HED can be calculated according to the formula:
`
`HED=animal dose in mg/kg x (animal weight in kg/human weight in kg)0
`
`33
`·
`
`.
`
`Noting the exponent in the formula, the relationship between the animal and human is not
`linearly related, as the Examiner assumed in her calculations.
`
`IV.
`
`Applying the results of the CDER formula does not achieve the
`dose in the claims
`In fact, as discussed above and in Appendix A on page 16 of the CDER, smaller
`rats than those used by Bartus are contemplated in Table 1 and the limitations and
`assumptions of the formula are discussed in detail. The application of the CDER's
`formula for a 50 mg/kg rat dose using 450 mg rats (Bartus) results in a starting dose of
`570 mg for a 54.5 kg human (HED of 10.46 x 54.5) and a starting dose of915 mg for a
`113.6 kg human (HED of8.05 x 113.6). Thus, if one were to apply the CDER formula as
`guidance to extrapolate a Sprague Dawley rat dose to humans, one would not arrive at the
`claimed dose range or an overlapping range.
`In any event, whether one calculates the dose as alleged by the Examiner or by
`the reference, the starting dose to establish safety exceeds the therapeutic dose taught by
`the claim, assuming the conversion is appropriate to calculate a therapeutic (not merely
`safe) dose for a depot formulation.
`
`1 The Examiner appears to concede in the Advisory Action that she was incorrect
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`If the CDER was the proper standard for determining the initial safety dose for a
`naltrexone microsphere from the Bartus rat study, then clearly the result achieved (an
`efficacious dose having twice the AUC of the FDA approved oral dose) would be
`unexpected because the claimed ranges are substantially lower than the CDER
`calculations. As explained in the CDER, one typically expects the efficacious dose in a
`human needing treatment would need to be more than the initial safety dose for healthy
`adult volunteers.
`Therefore, assuming the CDER is relevant to the calculations of a starting dose,
`the CDER suggests the invention achieved an unexpected result.
`Again, the Examiner now appreciates that the math is incorrect and her initial
`allegation that the claimed dose is merely the straightforward application of the CDER
`guidelines is also incorrect. That is, the CDER was cited to provide evidence as to how
`one selects a dose. Appellant established the Examiner was incorrect. Nonetheless, the
`Examiner pursues the rejection asserting that the dose and pharmacokinetic profile are
`still obvious, in spite of the fact that there is no evidence relevant to selecting this dose or
`pharmacokinetic profile.
`
`b. The CDER guidelines would not be assumed to apply to naltrexone
`microspheres
`Notwithstanding the above, the CDER sets forth guidelines which explicitly
`discuss reviewing all of the animal data available with respect to a drug and applying an
`algorithm based on the totality of the data, selecting the most relevant animal model for a
`first-in-humans clinical trial. Pages 3-4. The CDER does not advocate selecting a
`human dose from a single published rat model.
`The subject invention does not relate to a first-in-human clinical trial of
`naltrexone. At the time the present clinical trials were begun, naltrexone was already
`approved for human use at an oral dose of 50 mg/day. Bartus, for example, states that a
`disadvantage of oral human dosing is "widely fluctuating plasma levels" [Abstract, the
`Examiner's motivation for modifying the oral treatment regimen]. At the left hand
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`Application No. 13/871,534
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`column of page 1974 of Bartus, "daily fluctuations [in human plasma levels] may cause
`side effects during peak plasma levels." This suggests that, based on the available
`clinical data, there may be difficulties in human bioavailability and metabolism and that
`high peak plasma levels should be avoided. The starting point for determining a safe
`and/or efficacious dose of a long acting naltrexone formulation in humans would
`obviously be derived from the approved oral dose. Evidence Document 4 and 8,
`discussed in more detail below.
`Further, the CDER explicitly states the difficulties in using this algorithm, or
`simplified conversion formula, where human bioavailability and metabolism may differ
`significantly and mechanisms of toxicity may not be known. Footnote, Page 2. At Page
`3, the reference explicitly states that "[t]opical, intranasal, intratissue and compartmental
`administration routes and depot formulations can have additional considerations." See
`also Page 8.
`Figure 2 of Bartus illustrates that a burst in plasma levels can be observed in rats.
`Considering the warnings in the CDER, one may conclude from Bartus that dosing a
`human patient with naltrexone microspheres would require "additional considerations"
`including avoiding toxic levels during the peak, while maintaining therapeutic levels over
`a period of at least two weeks or a month, with a drug known to have widely fluctuating
`plasma levels upon oral administration. Thus, one of skill in the art would simply not be
`motivated to tum to the CDER guidelines, designed to provide a simple arithmetic
`estimation of a safe starting dose in an initial clinical trial in adult healthy volunteers
`based primarily on the weight ratio of one animal model and a human (the purpose of the
`CDER), much less to select an efficacious therapeutic dose for a depot formulation in
`alcohol dependent adults (the dose in the claim).
`As naltrexone is approved at a 50 mg/day oral dose, these studies would likely be
`determined a highly relevant study for calculating a human dose for a long acting
`formulation. Evidence Documents 4 and 8, discussed in more detail below.
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`c. Summary of the CDER
`In summary, the cited CDER reference teaches an algorithm that can be used in
`some instances to estimate maximum safe starting doses in first-in-human clinical trials
`(i.e. Phase I Clinical Trials). There is no reason to conclude that one of skill in the art
`would be motivated to tum to the CDER to select an efficacious dose for a long acting
`formulation of 380 mg, resulting in a serum AUC of twice the then currently available
`oral dosage form.
`Recognizing that the CDER did not teach the facts the Examiner alleged in the
`Final Office Action (that the claimed dose is a simple extrapolation ofBartus' rat dose),
`the Examiner asserts that the CDER provides general guidelines for establishing a human
`dose from animal models. However, the Examiner admits that the mathematics show
`that it is not true for the facts presented in this case. Thus, how the CDER supports the
`rejection, as compared to teaches away from the invention, is unclear.
`Even if it were true that those of skill in the art may extrapolate animal models for
`long acting naltrexone formulations to calculate initial safe doses in humans, it does not
`necessarily follow that the Examiner is excused from considering whether (1) the specific
`pharmacokinetic profile is obvious to select (e.g., at least twice the AUC of the approved
`oral dose) or (2) one of skill in the art would select the claimed dose (e.g., 380 mg) to
`achieve the selected pharmacokinetic profile or (3) whether the results are unexpected.
`Therefore, for all of the above reasons, the cited CDER reference regarding
`animal-to-human conversion factors for safe dosing in humans would not motivate a
`person having ordinary skill in the art to select the claimed dose. And, even if one were
`to follow the CDER guidelines as the Examiner has done, the dose would be substantially
`greater with an expectation of achieving a substantially lower AUC, not the inverse.
`Evidence Document 4.
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`9. Tice et al. suggest long acting formulations that achieve the same AUC as
`the oral dose is desirable (US Patent 6,306,425; Evidence Document 8)
`Tice et al. teach an injectable long acting naltrexone formulation comprising
`naltrexone in a poly (D,L-lactide) matrix with a small amount of residual ethyl acetate
`(Abstract) administered such that the microspheres release naltrexone over a period of at
`least 4 weeks in human subjects where the AUC in monitoring plasma levels similar to
`daily dosing of a 50 mg tablet. (Column 14, lines 26-64, column 15, lines 57-61; column
`16, lines 28-35; Evidence Document 4.) Tice et al. states that an objective of the long
`acting formulation is to allow less naltrexone to be administered. (Column 17, lines 1-
`1 0). Tice et al. do not teach that it is desirable to administer a dose of naltrexone that will
`result in 2 to 3 times the AUC of a 50 mg/day oral tablet.
`
`10. The cited prior art, combined, does not teach the claimed invention
`To establish a prima facie case of obviousness, three basic criteria must be met.
`First, there must be motivation to modify the reference or combine the references.
`Second a reasonable expectation of success must be established. Finally, the prior art
`must teach all of the limitations. In re Vaeck, 947 F.2d 488 (Fed. Cir. 1991).
`The Examiner appears to assert that one of skill in the art would be motivated to
`modify the oral dosing regimens of Heinala because, in short, Bartus teaches
`disadvantages with oral dosing and suggests injection with a PLGA long acting
`formulation can be beneficial. However, Heinala teaches that oral naltrexone can be
`administered on an as needed basis when alcohol craving is high. Leavitt reinforces
`these teachings. A long acting formulation will administer drug even when the craving is
`not high. Thus, the references are simply not combinable. In re Grasselli, 713 F.2d 731
`(Fed. Cir. 1983). The first prong of the three way test is not satisfied.
`However, even if one were to combine the references and conclude that one
`would modify the method of Heinala by substituting a long acting formulation for a daily
`oral dose, Bartus, Leavitt and Heinala do not teach how much of any specific long acting
`formulation one should administer or that the AUC should be selected to achieve at least
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`Application No. 13/871,534
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`twice that of the oral dose. In fact, Heinala suggests that 50 mg/day is not necessary but
`can be administered on an as needed basis after a couple of weeks.
`The Examiner appears to state on Page 7 of the Final Action that one would
`necessarily formulate a long acting formulation with "higher amounts of naltrexone to
`accommodate the amount of time the formulation is designed to last." Appellants do not
`disagree that a long acting formulation will typically have a "higher amount" of
`naltrexone as compared to a single oral dose (50 mg/day in this case). However, the
`issue is not simply whether the injectable dose should be higher than one oral dose. The
`issue is whether one of skill in the art would select a 190 or 380 mg dose, for example,
`and expect the injection of 190 or 3 80 mg of a naltrexone long acting formulation to
`achieve 2 or 3 times the serum AUC of a 50 mg/day oral dose. There is no suggestion to
`select a pharmacokinetic profile of twice Heinala's dose or a reasonable expectation of
`success as to how to achieve such a dose. In fact, the CDER, cited by the Examiner to
`allege this very proposition, would suggest that, if anything, the result is not the expected
`result. Additionally, Tice et al. suggests that one of ordinary skill in the art would select
`a similar serum AUC. Evidence Document 8. The fact that a 380 mg dose ofnaltrexone
`microspheres delivered a dose at three times the AUC of oral naltrexone was unexpected.
`Evidence Documents 1 and 4.
`Very simply, Bartus does not teach a human dose at all. Bartus presents the
`results in rats at 50 mg/kg. None of the prior art references cited in the rejection
`extrapolate a rat dose to a human dose for either oral administration or injection of
`naltrexone. None of the references teach or suggest that a pharmacokinetic profile of 2 or
`3 times the serum AUC of a 50 mg/day oral dose is desirabl