ATTORNEY DOCKET NO. 244168.000007.US.9
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Application of:
`
`Giorgio CALDERARI et al.
`
`Application No.: 13/901,830
`
`Filed: May 24,2013
`
`For: LIQUID PHARMACEUTICAL
`FORMULATIONS OF
`PALONOSETRON
`
`)
`)
`) Group Art Unit: 1628
`)
`)
`) Examiner: Shirley V. GEMBEH
`)
`)
`) Confirmation No.: 3806
`)
`)
`
`AMENDMENT AND RESPONSE TO OFFICE ACTION
`
`Commissioner of Patents
`United States Patent Office
`Alexandria, Virginia
`
`TROUTMAN SANDERS
`Customer Number 06980
`
`Dear Sir:
`In response to the Office Action mailed November 22, 2013, please consider the
`following Remarks.
`A Replacement Claim Set begins on page 2.
`Remarks begin on page 4.
`A Terminal Disclaimer is being filed concurrently herewith.
`
`I
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`I
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`I
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`I
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`21754693v1
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`L...------_11
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`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1023
`
`Exh. 1023
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`

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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 2 of 16
`
`REPLACEMENT CLAIM SET
`
`1-9)
`10)
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`11)
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`12)
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`13)
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`14)
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`15)
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`16)
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`17)
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`18)
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`(CANCELLED)
`(PREVIOUSLY PRESENTED) A pharmaceutical single-use, unit-dose formulation for
`intravenous administration to a human to reduce the likelihood of cancer chemotherapy-
`induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic solution
`buffered at a pH of 5.0 ± 0.5, said solution comprising:
`palonosetron hydrochloride in an amount of0.25 mg based on the weight of its free
`base;
`optionally a chelating agent; and
`from 10 mg/mL to 80 mg/mL mannitol,
`wherein said formulation is stable at 24 months when stored at room temperature.
`(PREVIOUSLY PRESENTED) The pharmaceutical formulation of claim 10, wherein
`said mannitol is in an amount of 41.5 mg/mL.
`(PREVIOUSLY PRESENTED) The pharmaceutical formulation of claim 10, wherein
`said solution further comprises a chelating agent.
`(PREVIOUSLY PRESENTED) The pharmaceutical formulation of claim 12, wherein
`said chelating agent is EDT A.
`(PREVIOUSLY PRESENTED) The pharmaceutical formulation of claim 13, wherein
`said EDTA is in an amount of from 0.005 mg/mL to 1.0 mg/mL.
`(PREVIOUSLY PRESENTED) The pharmaceutical formulation of claim 14, wherein
`said EDTA is in an amount of0.5 mg/mL.
`(PREVIOUSLY PRESENTED) The pharmaceutical formulation of claim 10, wherein
`said solution further comprises a citrate buffer.
`(PREVIOUSLY PRESENTED) The pharmaceutical formulation of claim 16, wherein
`said citrate buffer is at a concentration of 20 millimolar.
`(PREVIOUSLY PRESENTED) A pharmaceutical single-use, unit-dose formulation for
`intravenous administration to a human to reduce the likelihood of cancer chemotherapy-
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`21754693vl
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`Exh. 1023
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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 3 of 16
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`induced nausea and vomiting, compnsmg a 5 mL sterile aqueous isotonic solution
`buffered at a pH of 5.0 ± 0.5, said solution comprising:
`palonosetron hydrochloride in an amount of0.25 mg based on the weight of its free
`base;
`optionally a chelating agent; and
`from 10 mg/mL to 80 mg/mL mannitol,
`wherein said formulation is stable at 18 months when stored at room temperature.
`(NEW) The pharmaceutical formulation of claim 18, wherein said mannitol is in an
`amount of 41.5 mg/mL.
`(NEW) The pharmaceutical formulation of claim 18, wherein said solution further
`comprises a chelating agent.
`(NEW) The pharmaceutical formulation of claim 20, wherein said chelating agent is
`EDT A.
`(NEW) The pharmaceutical formulation of claim 21, wherein said EDTA is in an amount
`of from 0.005 mg/mL to 1.0 mg/mL.
`(NEW) The pharmaceutical formulation of claim 21, wherein said EDTA is in an amount
`of0.5 mg/mL.
`(NEW) The pharmaceutical formulation of claim 18, wherein said solution further
`comprises a citrate buffer.
`(NEW) The pharmaceutical formulation of claim 16, wherein said citrate buffer is at a
`concentration of 20 millimolar.
`
`19)
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`20)
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`21)
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`22)
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`23)
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`24)
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`25)
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`21754693vl
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`

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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 4 of 16
`
`REMARKS
`
`Claims 10-25 are currently pending in this application. Claims 1-9 were previously
`canceled without prejudice or disclaimer. Claims 10-18 were previously presented and are
`unamended. Claims 19-25 are newly presented. Because claims 19-25 mirror claims 11-17, but
`depend from claim 18 instead of claim 10, support for the new claims can be found in currently
`pending claims 11-1 7. No new matter is added by the amendment.
`
`REJECTION UNDER 35 U.S.C. § 103
`
`Claims 10-18 are rejected under pre-AIA1 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 of U.S.
`5,854,270 to Gambhir ("Gambhir") as evidenced by Matsumoto et al. "Manual for Practical
`Pharmacy" (1989) ("Matsumoto"). Office Action at pp. 3-8.
`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").
`Like the '219 patent, the current patent application claims a "single-use unit-dose
`formulation" of palonosetron hydrochloride. 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; and (2) a
`palonosetron hydrochloride concentration of 0.05 mg/mL (i.e., 0.25 mg in 5 mL). As argued
`
`1 Applicants respectfully submit that 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 of this application based on the pending
`rejections.
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`21754693vl
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`Exh. 1023
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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 5 of 16
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`below, 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.
`
`A.
`
`The Rejection Fails to Consider the Invention as a Whole
`
`Applicants disagree with the rejection firstly because the Office's primary reference,
`Berger, fails to suggest the claimed dose (0.25 mg), 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
`impermissible
`nature of the examination process. However,
`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 because it does not
`properly address the dose feature recited in the claims. The Office Action addresses the
`0.05 mg/mL concentration, and the obviousness of this concentration in view of Berger. 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." Office Action at p. 4. However, the claims are not limited solely to concentration; they
`also impose limitations on the actual dose of palonosetron hydrochloride in the formulation
`based on the weight of the free base (i.e., 0.25 mg). The claimed invention cannot be obvious
`unless the formulation as a whole, including the dose, would have been obvious, 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,
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`21754693vl
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`Exh. 1023
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`

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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 6 of 16
`
`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
`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 !lg/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 m the parent application, the currently pending claims define the
`palonosetron hydrochloride dose in the currently claimed formulation as 0.25 mg. The Office
`Action has failed to account for this feature 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.
`A Worker of Ordinary Skill Would Not Have Arrived at the Claimed
`B.
`Concentration and Dose via "Routine Experimentation/Optimization"
`
`propriety of usmg
`the
`question
`respectfully
`also
`Applicants
`"routine
`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. 4), 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, 11. 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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`Exh. 1023
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`

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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 7 of 16
`
`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 described 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, the breadth of Berger's 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 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. Teleflex, published at 75 Fed. Reg. 53643, at 53654 ("Guidelines"):
`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
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`Exh. 1023
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`

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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 8 of 16
`
`ordinary skill in the art could have pursued these known potential
`solutions with a reasonable expectation of success.
`
`According to this discussion, 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-McNeil Pharm., Inc. v. Mylan 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 1380, 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 106 choices. To be sure, Berger narrows the broad
`concentration range to encompass five orders of magnitude (i.e., "preferably 0.00001% w to
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`

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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 9 of 16
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`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 he or she would have faced that practically impossible task with absolutely nothing
`ointing 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 10 7 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 105 or 10 7 concentrations and 104 or 106 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 10 7
`orders of magnitude or Berger's broad dose ranges that span 104 and 106 orders of magnitude.
`
`C.
`
`A Species/Genus Theorv 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 107 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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`21754693vl
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`

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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 10 of 16
`
`(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, 11. 16-
`18 and 64-65.
`(b) Any "preferred" species or subgenus: in addition to those broad genera, Berger also
`recites a slightly smaller, but still 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, 11. 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, 11. 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 single 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, 11. 1-13. Thus, Berger, as illustrated
`immediately below, points the worker of ordinary skill to concentrations that are approximately
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`21754693vl
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`Exh. 1023
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`

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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 11 of 16
`
`200-2000 times higher than the claimed concentration, and to doses that are 40-400 times higher
`than the claimed dose:
`the final composition will compnse from
`(1) "In general,
`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 ng/day to 70 mg/day" (col. 12, 11. 16-18).
`
`(2) "preferably 0.00001% w to 1.0% w" (col. 12, 11. 66-67); and
`
`"preferably 700 ng/day to 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 mg/mL in intravenous formulations. See
`Application No. 13/901,437 (now U.S. Patent No. 8,598,219). 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,
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`Exh. 1023
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`

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`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 12 of 16
`
`which, as noted above, describes concentrations (10 to 100 mg/mL) that are 200-2000 times
`higher than the currently claimed 0.05 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).
`
`The Office's own rationale in that case was that nothing in Berger suggests moving
`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
`100 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, 11. 18-20; see also the '351 priority
`application at p. 11, 11. 22-24.
`A visual representation of that discovery is depicted in the following graph, which is
`adapted from a Figure of the Declaration ofDaniele Bonadeo dated February 9, 2009 (of record):
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`21754693vl
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`Exh. 1023
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`

`
`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 13 of 16
`
`tl<f.GRMl.~·tlGN
`~.~·tt;;, CG~~~lANf
`
`As can be seen from this Figure, Applicants unexpectedly discovered that as the
`concentration of palonosetron hydrochloride decreases from 5 mg/mL toward the presently
`claimed concentration, the palonosetron degradation rate decreases (follow the line on the right-
`hand side of the figure from back to front). See also Supplemental Declaration of Daniele
`Bonadeo (of record) at Exhibit 2 (demonstrating chemical instability of palonosetron
`hydrochloride at 10 mg/mL, which is the lower end of Berger's Example 13 range of
`concentrations).
`This stability of formulations compnsmg different concentrations of palonosetron
`hydrochloride was unpredictable. Indeed, Berger provided no reason to expect improved stability
`by lowering the palonosetron hydrochloride concentration. Thus, the unexpected stability of
`compositions comprising palonosetron hydrochloride at the presently claimed concentration of
`0.05 mg/mL could not have been reasonably predicted based on Berger's teachings.
`For all these reasons, Applicants respectfully submit that the obviousness rejection should
`be withdrawn.
`
`OBVIOUSNESS TYPE DOUBLE PATENTING
`
`The Office Action also rejects the pending claims based on obviousness-type double
`patenting over co-pending Application No. 14/052,925. Solely to advance prosecution of this
`application, Applicants submit herewith an additional Terminal Disclaimer over this application
`to obviate any putative double patenting issues. See M.P.E.P. § 804.02 ("The filing of a terminal
`disclaimer to obviate a rejection based on nonstatutory double patenting is not an admission of
`
`21754693vl
`
`Exh. 1023
`
`

`
`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 14 of 16
`
`the propriety of the rejection." (citing Quad Envtl. Techss Corp. v. Union Sanitary Dist., 946
`F.2d 870 (Fed. Cir. 1991)).)
`
`PATENTABLE WEIGHT OF INTENDED PURPOSE LIMITATION
`
`The Office contends "the limitations to reduce the likelihood of cancer chemotherapy-
`induced nausea and vomiting and is stable for 24 months and 18 months is given no patentable
`weight" for the reasons expressed in the Office Action at page 8, which are of record and will not
`be repeated here. Applicants respectfully disagree and do not admit the point. But, in view of the
`above explanation, the point is irrelevant to allowance.
`
`AlA STATUS
`
`Applicants note that the Application Data page for this application in the USPTO 's PAIR
`database designates the "AlA (First Inventor to File)" status of this application as "No."
`Similarly, Item 1 on page 2 of the Office Action states that "[t]he present application is being
`examined under the pre-AlA first to invent provisions." Applicants respectfully submit that the
`USPTO's designation of this application as a pre-AlA application is in error.
`As indicated on the Application Data Sheet, and as discussed in the Preliminary
`Amendment and Choice of Law document, both filed May 23, 2013, this application falls under
`transition provisions 3(n)(1)2 and 3(n)(2)3 of the America Invents Act (AlA) because claims 10-
`
`2 SEC. 3(n)(1): "Except as otherwise provided in this section, the amendments made by this
`section shall take effect upon the expiration of the 18-month period beginning on the date of the
`enactment of this Act [i.e., March 16, 2013}, and shall apply to any application for patent, and to
`any patent issuing thereon, that contains or contained at any time- (A) a claim to a claimed
`invention that has an effective filing date as defined in section 100(i) of title 35, United States
`Code, that is on or after the effective date described in this paragraph [i.e., March 16, 2013}; or
`(B) a specific reference under section 120, 121, 365(c) of title 35, United States Code, to any
`patent or application that contains or contained at any time such claim." (Commentary added for
`emphasis.)
`
`3 SEC. 3(n)(2): "The provisions of sections 102(g), 135, and 291 of title 35, United States Code,
`as in effect on the day before the effective date set forth in paragraph (1) of this subsection [i.e.,
`March 15, 2013}, shall apply to each claim of an application for patent, and any patent issued
`thereon, for which the amendments made by this section also apply, if such application or patent
`
`21754693vl
`
`Exh. 1023
`
`

`
`U.S. Application No. 13/901,830
`Amendment and Response to Office Action
`February 21, 2014
`Page 15 of 16
`
`18 have an effective filing date ("EFD") prior to March 16, 2013, and the parent CIP application
`contained a claim (original claim 9) that found support under 35 U.S.C. § 112 only in Example 8,
`which was newly added to the parent continuation-in-part application. Thus, claim 9 had an EFD
`after March 15, 2013.
`In other words, this application is popularly referenced as a Jedi Master Mixer (JMM).
`The Examiner expressly acknowledged that phrase in the Interview Summary of June 13, 2013
`in Application No. 13,087: "Applicant explained why there is no on sale bar also discussed 6
`other pending applications, 4 of which are JMM. According to the USPTP POSITION THE
`ALLEGED ON SALE BARS DO NOT APPLY TO THE JMM applications .. For disclosure
`JMM means Jedi Master Mixer."
`For that reason, all of claims 10-18 should, for prior art purposes, be examined only
`through the lenses of AlA§§ 102(a)(1), (a)(2), and 103, as well as pre-AlA§ 102(g). That point
`is clearly explained by the USPTO:
`If an application (1) contains or contained at any time a claimed
`invention having an effective filing date that is before March 16,
`2013, or ever claimed a right of priority or the benefit of an earlier
`filing date under 35 U.S.C. 119, 120, 121, or 365 based upon an
`earlier application that ever contained a claimed invention having
`an effective filing date that is before March 16, 2013 [such as
`claims 1 0-18}, and (2) also contains or contained at any time any
`claimed invention having an effective filing date that is on or after
`March 16, 2013, or ever claimed a right of priority or the benefit of
`an earlier filing date under 35 U.S.C. 119, 120, 121, or 365 based
`upon an earlier application that ever contained a claimed invention
`having an effective fili