ATTORNEY DOCKET NO. 244168.000007USJO
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Application of:
`
`Giorgio CALDERARJ et at.
`
`Application No.: 13/902,132
`
`Filed: May 24, 2013
`
`For: LIQUID PHARMACEUTICAL
`FORMULATIONS OF
`PALONOSETRON
`
`)
`)
`) Group Art Unit: 1628
`)
`)
`) Examiner: Shirley V. GEMBEH
`)
`)
`) Confinnation No.: 2532
`)
`)
`
`AMENDMENT AFTER FINAL
`
`Commissioner of Patents
`United States Patent Office
`Alexandria, Virginia
`
`TROUTMAN SANDERS
`Customer Number 06980
`
`Dear Sir:
`In reply to the Office Action mailed December 6, 2013, please consider the Remarks
`presented herein.
`Amendments to the Claims are reflected in the listing of claims in this paper.
`Remarks begin on page 6.
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`Active 21754957v1
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`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1009
`
`Exh. 1009
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`

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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 2 of 19
`
`AMENDMENTS TO THE CLAIMS
`(CANCELLED)
`1-11.
`12.
`(PREVIOUSLY PRESENTED) A method for reducing the likelihood of cancer
`chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human
`in need thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL sterile
`aqueous isotonic solution buffered at a pH of about 5.0 ± 0.5, said solution comprising:
`about 0.05 mg/mL palonosetron hydrochloride based on the weight of its free base;
`about 41.5 mg/mL mannitol;
`about 0.5 mg/mL EDTA; and
`a citrate buffer,
`wherein said formulation is stable at 24 months when stored at room temperature, and
`wherein said intravenous administration to said human occurs before the start of the
`cancer chemotherapy.
`13.
`(PREVIOUSLY PRESENTED) The method of claim 12, wherein said
`intravenous administration to said human occurs over a period of time of 10 to 60 seconds.
`(PREVIOUSLY PRESENTED) The method of claim 12, wherein said
`14.
`intravenous administration reduces the likelihood of acute nausea and vomiting in said human.
`15.
`(PREVIOUSLY PRESENTED) The method of claim 12, wherein said
`intravenous administration reduces the likelihood of delayed nausea and vomiting in said human.
`16.
`(PREVIOUSLY PRESENTED) A method for reducing the likelihood of cancer
`chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human
`in need thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL sterile
`aqueous isotonic solution buffered at a pH of about 5.0 ± 0.5, said solution comprising:
`about 0.05 mg/mL palonosetron hydrochloride based on the weight of its free base;
`from about 10 mg/mL to about 80 mg/mL mannjtol; and
`from about 0.3 mg/mL to about 0.7 mg/mL EDTA;
`wherein said solution optionally comprises a citrate buffer,
`wherein said formulation is stable at 24 months when stored at room temperature, and
`wherein said intravenous administration to said human occurs before the start of the
`cancer chemotherapy.
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 3 of 19
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`(PREVIOUSLY PRESENTED) The method of claim 16, wherein said
`17.
`intravenous administration to said human occurs over a period of time of 10 to 60 seconds.
`18.
`(PREVIOUSLY PRESENTED) The method of claim 16, wherein said
`intravenous administration reduces the likelihood of acute nausea and vomiting in said human.
`(PREVIOUSLY PRESENTED) The method of claim 16, wherein said
`19.
`intravenous administration reduces the likelihood of delayed nausea and vomiting in said human.
`20.
`(PREVIOUSLY PRESENTED) The method of claim 16, wherein said solution
`comprises from about 20 mg/mL to about 60 mg/mL mannitol.
`21.
`(PREVIOUSLY PRESENTED) The method of claim 20, wherein said solution
`comprises from about 40 mg/mL to about 45 mg/mL mannitol.
`22.
`(PREVIOUSLY PRESENTED) The method of claim 21, wherein said solution
`comprises about 41.5 mg/mL mannitol and about 0.5 mg/mL EDT A.
`23.
`(PREVIOUSLY PRESENTED) The method of claim 16, wherein said solution
`comprises a citrate buffer.
`24.
`(PREVIOUSLY PRESENTED) A method for reducing the likelihood of cancer
`chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human
`in need thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL sterile
`aqueous isotonic solution, said solution comprising:
`about 0.05 mg/mL palonosetron hydrochloride based on the weight of its free base;
`a tonicifying effective amount of mannitol; and
`from about 0.3 mg/mL to about 0.7 mg/mL EDTA;
`wherein said solution optionally comprises a citrate buffer and optionally has a pH of
`from about 5.0 ± 0.5,
`wherein said formulation is stable at 24 months when stored at room temperature, and
`wherein said intravenous administration to said human occurs before the start of the
`cancer chemotherapy.
`25.
`(PREVIOUSLY PRESENTED) The method of claim 24, wherein said
`intravenous administration to said human occurs over a period of time of 10 to 60 seconds.
`26.
`(PREVIOUSLY PRESENTED) The method of claim 24, wherein said
`intravenous administration reduces the likelihood of acute nausea and vomiting in said human.
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 4 of 19
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`27.
`(PREVIOUSLY PRESENTED) The method of claim 24, wherein said
`intravenous administration reduces the likelihood of delayed nausea and vomiting in said human.
`28.
`(PREVIOUSLY PRESENTED) The method of claim 24, wherein said solution
`comprises a citrate buffer.
`29.
`(PREVIOUSLY PRESENTED) The method of claim 24, wherein said solution is
`buffered at a pH of about 5.0 ± 0.5.
`30.
`(PREVIOUSLY PRESENTED) The method of claim 24, wherein said solution
`comprises from about 10 mg/mL to about 80 mg/mL mannitol.
`31.
`(PREVIOUSLY PRESENTED) The method of claim 30, wherein said solution
`comprises from about 20 mg/mL to about 60 mg/mL mannitol.
`(CURRENTLY AMENDED) The method of claim ~ .ll, wherein said solution
`32.
`comprises about 41.5 mg/mL mannitol and about 0.5 mg/mL EDT A.
`33.
`(PREVIOUSLY PRESENTED) A method for reducing the likelihood of cancer
`chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human
`in need thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL sterile
`aqueous isotonic solution buffered at a pH of about 5.0 ± 0.5, said solution comprising:
`about 0.05 mg/mL palonosetron hydrochloride based on the weight of its free base; and
`a tonicifying effective amount of mannitol;
`wherein said solution optionally comprises one or a combination of a citrate buffer and a
`chelating agent,
`wherein said formulation is stable at 24 months when stored at room temperature, and
`wherein said intravenous administration to said human occurs before the start of the
`cancer chemotherapy.
`34.
`(PREVIOUSLY PRESENTED) The method of claim 33, wherein said
`intravenous administration to said human occurs over a period of time of 10 to 60 seconds.
`35.
`(PREVIOUSLY PRESENTED) The method of claim 33, wherein said
`intravenous administration reduces the likelihood of acute nausea and vomiting in said human.
`36.
`(PREVTOUSLY PRESENTED) The method of claim 33, wherein said
`intravenous administration reduces the likelihood of delayed nausea and vomiting in said human.
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 5 of 19
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`37.
`(PREVIOUSLY PRESENTED) The method of claim 33, wherein said solution
`comprises a citrate buffer.
`38.
`(PREVIOUSLY PRESENTED) The method of claim 33, wherein said solution
`comprises a chelating agent.
`39.
`(PREVIOUSLY PRESENTED) The method of claim 38, wherein said chelating
`agent iis EDT A.
`40.
`(PREVIOUSLY PRESENTED) The method of claim 39, wherein said solution
`comprises from about 0.3 mg/rnL to about 0.7 mg/rnL EDT A.
`41.
`(PREVIOUSLY PRESENTED) The method of claim 33, wherein said solution
`comprises from about 10 mg/mL to about 80 mg/rnL mannitol.
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 6 of 19
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`Status of the Claims
`
`REMARKS
`
`Claims 12-41 are currently pending in this application. Claims 1-11 were previously
`cancelled without prejudice or disclaimer. Claim 32 is amended herein to correct a typographical
`error in its dependency. Thus, this amendment does not add new matter.
`
`Objections to Claims
`
`The Office objects to claim 27 as a duplicate of claim 26. Applicants have analyzed the
`claims, and believe that there is a difference between these claims due to the recitation of
`delayed emesis in claim 27 and acute emesis in claim 26. These are two different stages of
`emesis and they are distinct because acute emesis occurs in the first 24 hours following
`chemotherapy, while delayed emesis occurs during hours 25-120 following chemotherapy. See,
`e.g., Sabra, K. Choice of a 5HT3 Receptor Antagonist for the Hospital Formulary, EHP, Oct.
`1996; 2(suppl 1):S19-24 (cited in the as-filed specification at p. 3, 11. 1-2, and submitted as IDS
`Reference No. 663). These two phases of emesis are discussed in the background of the
`specification at pages 2-3, and are well-known to oncologists and others who practice cancer
`supportive care. In view of this distinction, Applicants respectfully submit that the claims are
`directed toward distinct subject matter.
`
`Rejections Under 35 U.S.C. § 103
`
`The Office rejects claims ] 2, 14-16, 18-24, 26-33, and 35-41 under post-AlA 1 35 U.S.C.
`§ 103 as obvious over U.S. 5,202,333 to Berger et al. ("Berger") in view of Barton '·'Citric Buffer
`Calculation" (2000) ("Barton") and U.S. 6,284,749 to Castillo et al. ("Castillo"), and further in
`view ofU.S. 5,854,270 to Gambhir ("Gambhir") as evidenced by Matsumoto et aL "Manual for
`Practical Pharmacy" (1989) ("Matsumoto"). The Office rejects claims 13, 17, and 25, based on
`
`1 As indicated in PAJR, this case should be examined under post-AlA 35 U.S.C. § 103, because it claims
`priority to an application that presented a claim that has a priority date after March 16, 2013. See also the
`"AlA Status" section below. Nevertheless, Applicants do not believe that the AlA has any impact on the
`examination ofthis application based on the pending rejections.
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 7 of 19
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`the foregoing rationale, and further in view of Landau et al. (US 2004/014 77 51 0) and Perez et al.
`(Cancer J. Sci Am (1998) 4(1):52).2
`As an initial matter, Applicants note that they have prosecuted several applications in the
`same family as this application. Those applications have resulted in patents directed toward
`pharmaceutically stable intravenous solutions of palonosetron hydrochloride, single-use unit-
`dose formulations of palonosetron hydrochloride, and methods of making single unit dose vials
`of palonosetron hydrochloride. See, e.g., U.S. 7,947,724 (claiming "stable intravenous
`solution"); U.S. 8,598,219 (claiming "single-use, unit-dose formulation"); and U.S. 8,598,218
`(claiming "method of manufacturing and terminally sterilizing").
`The current patent application differs from those earlier applications at least because it
`claims a method of using palonosetron hydrochloride formulations to treat emesis induced by
`chemotherapy ("CINV"). However, for purposes of this examination, all of the claims also recite
`(directly or indirectly): (1) a 0.25 mg dose ofpalonosetron hydrochloride based on the weight of
`its free base (i.e., 0.05 mg/mL in 5 mL) and (2) a palonosetron hydmchloride concentration of
`0.05 mg/mL. Applicants respectfully submit that these features were not obvious when this
`invention was made, and that these features further support the patentability of the claimed
`invention.
`The Office Action does not address the claimed dose, but addresses the concentration of
`palonosetron hydrochloride in the formulation. In particular, the Office Action concludes that
`Berger renders the 0.05 mg/mL concentration obvious because Berger teaches palonosetron
`concentrations "from 0.000001% w to 10% weight" and, "where the general conditions of a
`claim are disclosed in the prior art, it is not inventive to discover the optimum or workable
`ranges by routine experimentation. In re Aller, 220 F.3d 454,456, 105 USPQ 233, 235 (CCPA
`1955)." Office Action at pp. 5 and 9.
`For the reasons given below, Applicants traverse the rejection.
`
`2 Applicants assume that the Office intended also to include claim 34 in this aspect of the rejection.
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 8 of 19
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`A. The Rejection Fails to Properly Consider the Concentration and Dose Recited in all
`the Claims
`
`As a preliminary matter, Applicants disagree with the rejection because the Office's
`primary reference, Berger, fails to suggest the claimed concentration and dose, and hence, fails to
`account for the invention as a whole. As stated in MPEP 2142:
`
`To reach a proper determination under 35 U.S.C. 103, the examiner must
`step backward in time and into the shoes worn by the hypothetical "person
`of ordinary skill in the art" when the invention was unknown and just before
`it was made. In view of all factual information, the examiner must then
`make a determination whether the claimed invention "as a whole" would
`have been obvious at that time to that person. Knowledge of applicant's
`disclosure must be put aside in reaching this determination, yet kept in mind
`in order to determine the "differences," conduct the search and evaluate the
`"subject matter as a whole" of the invention. The tendency to resort to
`"hindsight" based upon applicant's disclosure is often difficult to avoid due
`to the very nature of the examination process. However, impermissible
`hindsight must be avoided and the legal conclusion must be reached on the
`basis of the facts gleaned from the prior art.
`
`The Office Action does not account for the invention as a whole at least because it does
`not properly address both the dose and concentration features recited in the claims. The Office
`Action addresses the 0.05 mg/mL concentration, and the obviousness of this concentration in
`view of Berger. However, the claims are not limited solely to concentration; they also impose
`limitations on the dose (mg) of palonosetron hydrochloride in the formulation based on the
`weight of the free base by reciting a volume limitation (5 mL) which, when multiplied by the
`concentration of 0.05 mg/mL gives a 0.25 mg dose. The claimed method cannot be obvious
`unless the administered formulation as a whole, including the dose, would have been obvious in
`the context of the method of treatment being claimed, which for the reasons discussed in the
`remainder of this paper, it clearly is not.
`Importantly. the palonosetron hydrochloride dose recited in the currently pending claims
`was addressed previously during the prosecution of the parent continuation-in-part application,
`now U.S. Patent No. 8,958,219, and was cited specifically in the Reasons for Allowance as a
`basis for allowing that case. That application, like the currently pending claims, included a dose
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 9 of 19
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`limitation of 0.25 mg palonosetron hydrochloride based on the weight of its free base. As stated
`in the Reasons for Allowance in the parent application:
`
`The closest prior art Tang (Anesth Analg 1998; 87 462-467; Ref 105 on
`May 23, 2013) specifically teach that implications in administering
`palonosetron (i.e., RS-25259) was effective only at a higher dose (i.e. 30
`f.!g/kg which is 2.1 when an average weight 70 kg of the patient is
`considered). This dose is far greater than that recited by the applicant. Yes
`Tang teaches a concentration of 3.0 ug/kg which is the closest to the dose
`recited, however Tang also teaches that it fails to provide or reduce the post-
`operative vomiting.
`
`Like the claims in the parent application, a combination of features recited in the currently
`pending claims defines the palonosetron hydrochloride dose administered in the currently
`claimed method. These features include a 5 mL volume and a 0.05 mg/mL concentration, which
`equate to a 0.25 mg dose based on the weight of the free base. The Office Action has failed to
`account for this combination of features and thus, has failed to address the invention "as a
`whole." As a consequence, the references do not support a prima facie case of obviousness, and
`the rejection should be withdrawn.
`
`B. A worker of ordinary skiU would not have arrived at the claimed concentration and
`dose via "routine experimentation/optimization"
`
`respectfully
`also
`Applicants
`"routine
`propriety of usmg
`the
`question
`experimentation/optimization" as the basis for rejecting the claims. There is nothing routine
`about going from Berger's broad concentration and dosing ranges to the specific concentration
`and dose recited in the claims. This would have required an enormous amount of work, with
`absolutely no guarantee of success and no direction leading to the concentration and dose recited
`in the claims.
`With respect to concentration, Berger describes a "general" concentration range spanning
`seven orders of magnitude (i.e., "from 0.000001 % w to 10.0% w"; col. 12, 11. 64-65; see also
`Office Action at p. 5), and subsequently leads the worker of ordinary skill to a preferred
`concentration range that spans five orders of magnitude (i.e., "preferably 0.00001% w to 1.0%
`w"; col. 12, ll. 66-67), and eventually to a concentration range of 10-100 mg/mL in Example 13.
`It would have taken an enormous amount of work, and would have been practically impossible,
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 10 of 19
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`to go from the wide concentration ranges disclosed by Berger to the 0.05 mg/mL concentration
`described in the claims, especially when Berger's only exemplified intravenous concentration
`range in Example 13 (10-100 mg/mL) is 200-2,000 times greater than the 0.05 mg/mL
`concentration described in the claims. The concentration range in Example 13 would have led a
`worker of ordinary skill away from the claimed invention.
`Berger also does not provide adequate dosing guidance to support a "routine
`experimentation" rejection. Applicants' claims are limited to a very specific dose of 0.25 mg.
`However, Berger gives a much broader range, stating in column 12, lines 11-18 that:
`
`[A] therapeutically effective amount for a 70 Kg human may range from 70
`ng/day to 70 mg/day, preferably 700 ng/day to 7.0 mg/day.
`
`Thus, Berger describes a general dose range spanning six orders of magnitude (i.e., "from 70
`ng/day to 70 mg/day"), and subsequently leads the worker of ordinary skill to a preferred dose
`range that spans four orders of magnitude (i.e., 700 ng/day to 7.0 mg/day), and eventually to a
`dose range of 10-100 mg/day in Example 13. Once again, it would have taken an enormous
`amount of work, and would have been practically impossible, to go from Berger's large range of
`doses to the 0.25 mg dose recited in the claims, particularly when the 0.25 mg dose falls well
`below the only exemplified intravenous dose of 10-100 mg descriibed by Example 13. Once
`again, Berger's Example 13 teaches away from the claimed invention.
`Because of the large amount of work needed to go from Berger's broad concentration
`disclosure, and broad dosing disclosure, and because there was absolutely no guidance in Berger
`leading to either the claimed concentration or the claimed dose, it would have taken far more
`than "routine experimentation" to arrive at the claimed 0.05 mg/mL concentration and 0.25 mg
`dose.
`
`The doctrine of "routine experimentation" cannot be applied to the pending claims for
`additional reasons. In particular, the concept of "routine experimentation" can be found in the
`Office's KSR Examination Guidelines in its "obvious to try" discussion, which makes clear that
`the doctrine is very limited. As stated in the Examination Guidelines Update: Developments in
`the Obviousness Inquiry After KSR v. Telejlex, published at 75 Fed. Reg. 53643, at 53654
`("Guidelines"):
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 11 of 19
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`This rationale is only appropriate when there is a recognized problem or
`need in the art; there are a finite number of identified, predictable solutions
`to the recognized need or problem; and one of ordinary skill in the art could
`have pursued these known potential solutions with a reasonable expectation
`of success.
`
`As this discussion makes clear, the "obvious to try" rationale is only appropriate when there are a
`finite number of predictable solutions. Berger's broad concentration ranges spanning five and
`seven orders of magnitude, and Berger's broad dose ranges spanning four and six orders of
`magnitude, are, for practical purposes, anything but a finite number of predictable solutions. See
`Guidelines at 53655, 53660 (citing Ortho-AfcNeil Pharm., Inc. v. l'.1ylan Labs, Inc. 520 F.3d
`1358 (Fed. Cir. 2008), which notes that "several" unpredictable alternatives is not a "finite
`number of identified, predictable solutions," and "several" is certainly far less than 104, 105, 106,
`and 10\ see also Wyeth and Cordis Corp. v. Abbott Labs., 720 F.3d B80, 1385 (Fed. Cir. 2013)
`(noting, in the context of an enablement analysis, that "having to synthesize and screen each of at
`least tens of thousands of candidate compounds constitutes undue experimentation.").
`The MPEP elaborates further on the "obvious to try" doctrine, and gives two classes of
`situations in section 2143 in which it is improper to apply an "obvious to try" rationale.
`According to MPEP 2143, the Office should not use an obvious to try rationale to reject an
`application:
`
`(1) when what would have been "obvious to try" would have been to vary
`all parameters or try each of numerous possible choices until one possibly
`arrived at a successful result, where the prior art gave either no indication of
`which parameters were critical or no direction as to which of many possible
`choices is likely to be successful; and
`
`(2) when what was "obvious to try" was to explore a new technology or
`general approach that seemed to be a promising field of experimentation,
`where the prior art gave only general guidance as to the particular form of
`the claimed invention or how to achieve it.
`
`Both of those situations apply here. Berger, as noted, provides a "general" range of
`concentrations that spans seven orders of magnitude (i.e., 0.000001% w to 10.0% w), involving
`at least 107 choices, and a broad range of doses that spans six orders of magnitude (i. e.,
`70 ng/day to 70 mg/day), involving at least I 06 choices. To be sure, Berger narrows the broad
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 12 of 19
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`concentration range to encompass five orders of magnitude (i.e., "preferably 0.00001% w to
`1.0% w," col. 12, 11. 66-67), involving at least 105 choices, and narrows the broad dose range to
`encompass four orders of magnitude (i.e., "preferably 700 ng/day to 7.0 mg/day"), involving at
`least 104 choices.
`But to arrive at the presently claimed concentration and dose, the worker of ordinary
`skill would have had to try a practically infinite number of possible choices of concentrations
`and doses. And she would have faced that practically impossible task with absolutely nothing
`pointing her towards the presently claimed concentration of 0.05 mg/mL or the presently claimed
`dose of 0.25 mg. Berger's general guidance providing a range of 105 or 107 concentrations and a
`range of 104 or 106 doses is no reasonable guidance at all.
`The Federal Circuit has made clear that when the worker of ordinary skill would have
`merely been "throwing metaphorical darts at a board in hopes of arriving at a successful result,"
`an invention is not obvious. In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig., 676 F.3d 1063, 1071 (Fed. Cir. 2012) (internal citations omitted). This rejection
`falls precisely within that situation, where the Office's primary reference gives an immense
`number of possible choices spanning at least 1 05 or 10 7 concentrations and 104 or 1 06 doses, and
`is totally devoid of any direction to arrive at the presently claimed concentration of 0.05 mg/mL
`or the presently claimed dose of0.25 mg.
`The secondary references cited by the Office fail to cure Berger's deficiency; none of
`those references even deals with palonosetron hydrochloride, much less indicates to the worker
`of ordinary skill any direction within Berger's broad concentration ranges that span 105 and 107
`orders of magnitude or Berger's broad dose ranges that span 104 and 106 orders ofmagnitude.
`
`C. A Species/Genus Theory of Obviousness Does Not Apply to the Claims
`
`The fact that the claimed concentration of 0.05 mg/mL and the claimed dose of 0.25 mg
`(both species) are encompassed by Berger's broad genera of 105 and 10 7 concentrations and 104
`and 106 doses is not sufficient by itself to establish a prima facie case of obviousness. See
`M.P.E.P. § 2144.08. The Office must establish that the worker of ordinary skill would have been
`motivated to select the claimed concentration and dose from Berger's broad disclosure. !d. The
`factors that must be considered include, for example:
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 13 of 19
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`(a) The size of the genus: Berger's genera are enormously broad, encompassing a range
`of concentrations spanning seven orders of magnitude (i.e., 107 % wand at least 107 choices) and
`a range of doses spanning six orders of magnitude (i.e., 70 ng/day to 70 mg/day). Col. 12, ll. 16-
`18 and 64-65.
`(b) Any "preferred" species or subgenus: in addition to those broad genera, Berger also
`recites a slightly smaller, but sti II practically infinite, range of concentrations spanning five
`orders of magnitude (i.e., "preferably 0.00001 % w to 1.0% w"), and a slightly smaller, but still
`practically infinite, range of doses spanning four orders of magnitude (i.e., "preferably 700
`mg/day to 7.0 mg/day"). Col. 12, ll. 18 and 64-67.
`(c) Any other express teachings: Berger exemplifies a single representative intravenous
`formulation, itself having a range of concentrations of active ingredients spanning 1% w to
`10% wand a range of doses spanning 10 mg to 100 mg (i.e., "10-100 mg" in "1 mL"). Example
`13, col. 29, ll. 1-13. That example, of course, moves in an opposite direction within Berger's
`broad concentration and dose ranges compared to the much LOWER claimed concentration of
`0.05 mg/mL and the much LOWER claimed dose of0.25 mg.
`(d) The significance of the differences between the prior art and the claimed invention:
`The differences between Berger's disclosure and the claimed invention are significant. For
`example:
`First, Berger's general range of concentrations spans at least 107 possibilities, and
`Berger's preferred range spans at least 105 possibilities. Similarly, Berger's general range of
`doses spans at least 106 possibilities, and Berger's preferred range spans at least 104 possibilities.
`In contrast, the present claims recite a single concentration of 0.05 mg/mL and a s.ingle dose of
`0.25 mg. Thus, Berger's disclosed ranges, which span 105 and 107 concentrations and 104 and 106
`doses, are infinitely broader, from a practical point of view, than the claimed specific
`concentration.
`Second, Berger only exemplifies one intravenous formulation, and that formulation is
`disclosed as having a range of concentrations spanning 10 to 100 mg/mL and a range of doses
`spanning 10 to 100 mg. See Example 13, col. 29, II. 1-13. Thus, Berger, as illustrated
`immediately below, points the worker of ordinary skill to concentrations that are approximately
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`U.S. Application No. 13/902,132
`Amendment After Final
`February 21, 2014
`Page 14 of 19
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`200-2000 times higher than the claimed concentration, and to doses that are 40-400 times higher
`than the claimed dose:
`
`(1) "In general, the final composition will comprise from
`0.000001% w to 10% w" (col. 12, 11. 64-65); and
`
`"a therapeutically effective amount for a 70 Kg human may range
`from 70 nfYday to 70 mfYdal
`(coL 12, 11. 16-18).
`
`(2) "preferably 0.00001% w to 1.0% w" (col. 12, ll. 66-67); and
`
`"preferably 700 ng/day ot 7.0 mg/day" (col. 12, ln. 18).
`
`!
`
`(3) only exemplified composition for intravenous administration:
`1% w to 10% w concentrations and 10 mg to 100 mg doses (i.e.,
`10-100 mg in 1 mL) (Example 13).
`
`As is well established, "[e]vidence that others were 'going in different ways' is strong
`evidence that the [inventor's] way would not have been obvious ." In re Cyclobenzaprine
`Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1082 (Fed. Cir. 2012)
`(citing Panduit Corp. v. Dennison Mfg. Co., 774 F.2d 1082, 1099 (Fed. Cir. 1985), which
`M.P.E.P. § 2144.08 cites with approval for other reasons).
`In fact, the Office has already correctly recognized that Berger directs toward
`concentrations of 10 to 100 mg/mL and thus would have led the worker of ordinary skill away
`from using the claimed concentration of 0.05 mglmL in intravenous formulations. See
`Application No. 13/901,437 (now U.S. Patent No. 8,598,219).
`Indeed, in the Interview Summary for that application, the Office stated, in distinguishing
`the 0.25 mg/5 mL (i.e., 0.05 mg/mL) palonosetron hydrochloride concentration recited in those
`claims, that Berger describes "high concentrations." The Office supported that conclusion by
`referencing Berger's Example 13, which, as noted above, describes concentrations (10 to
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`Amendment After Final
`February 21, 2014
`Page 15 of 19
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`that are 200-2000 times higher than the currently claimed 0.05 mg/mL
`100 mg/mL)
`concentration:
`
`This is commensurate with the low concentration described in the
`claims (0.25 mg/5 mL) relative to
`the high concentrations
`described in the prior art (Berger 5,202,3 [3]3, Example 13).
`
`Application No. 13/901,437, Interview Summary (emphasis added).
`The Office's own rationale in that case was that nothing in Berger suggests movmg
`within Berger's broad range of concentrations, from the high concentrations exemplified in
`Example 13 to the low claimed concentrations. Rather, the Office's rationale indicates that
`Berger's high concentrations, such as those specifically exemplified (i.e., 10 mg/mL and
`1 00 mg/mL ), would have moved
`the worker of ordinary skill away from
`the
`lower
`concentrations encompassed within Berger's vast range of general concentrations (and hence
`also away from concentrations such as the presently claimed concentration of 0.05 mg/mL), and
`towards far higher concentrations.
`There is thus no rationale of record that would have motivated the worker of ordinary
`skill to decrease Berger's exemplified range of high concentrations for intravenous formulations
`and thereby obtain the presently claimed concentration. Rather, as the Office has acknowledged,
`Berger would have led away from the presently claimed 0.05 mg/mL.
`(e) The unpredictability of the technology: stability of formulations compnsmg
`palonosetron hydrochloride in the presently claimed concentration was unpredictable. For
`example:
`As discussed! in Example 2 of the instant specification, a formulation optimization study
`was performed using experimental design software. Twenty-four lots of drug product were
`analyzed to investigate, inter alia, the appropriate concentration ranges for palonosetron
`hydrochloride.
`The results of that study indicated that palonosetron hydrochloride concentration was a
`critical factor in chemical stability, "with greatest stability seen at the lowest palonosetron
`hydrochloride concentrations." As-filed specification at p. 13, ll. 18-20; see also the '351 priority
`application at p. 11, 11. 22-24.
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`Amendment After Final
`February 21, 2014
`Page 16 of 19
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`A visual representation of that discovery is depicted