Ex Parte Dey et alDownload PDFPatent Trial and Appeal BoardOct 16, 201814152000 (P.T.A.B. Oct. 16, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 14/152,000 01/10/2014 144695 7590 10/16/2018 Ewers & Hasselmann PLLC 1101 Connecticut Avenue NW, Suite 450 Washington, DC 20036 FIRST NAMED INVENTOR Michael Dey UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www .uspto.gov ATTORNEY DOCKET NO. CONFIRMATION NO. 2115-1002-N 7065 EXAMINER BROWN-PETTIGREW, ANGELA C ART UNIT PAPER NUMBER 1621 MAIL DATE DELIVERY MODE 10/16/2018 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte MICHAEL DEY, JOEL RICHARD, MARIE-MADELEINE BARONNET, NATHALIE MONDOLY, LAURENT BERTOCCHI, and JEREMIAH HARNETT Appeal2017-004020 Application 14/152,000 Technology Center 1600 Before FRANCISCO C. PRATS, JEFFREY N. FRED MAN, and DEBORAH KATZ, Administrative Patent Judges. KATZ, Administrative Patent Judge. DECISION ON APPEAL Appeal2017-004020 Application 14/152,000 Appellants 1 seek our review, under 35 U.S.C. § I34(a), of the Examiner's decision to reject claims 1-3, 5-7, 11-14, and 17. (Appeal Brief ("App. Br.") 1.) We have jurisdiction under 35 U.S.C. § 6(b). We affirm. The Examiner rejected claims 1-3, 5-7, 11-14, and 17 as being obvious under 35 U.S.C. I03(a) over Quay2 and Burczynski. 3 (See Final Office Action issued December 17, 2015 ("Final Act.") 3-6; Examiner's Answer issued November 14, 2016 ("Ans.") 2-5.) Appellants' specification is directed to a formulation of apomorphine, a drug previously known to be used for treating patients with advanced Parkinson's disease, when formulated in a solution suitable for subcutaneous infusion and injection. (See Specification ("Spec.") 1: 14--20.) Appellants report that these routes of administration can cause injection site reactions when the apomorphine precipitates and chemically degrades under physiological conditions and pH. (See Spec. 1:21-26.) To address these concerns, Appellants report that their formulation has a pH "close to the physiological pH," which stabilizes increased concentrations of the drug and makes them suitable for parenteral4 subcutaneous administration. (Spec. 1:32-2:2.) 1 Appellants report that the real party in interest is Britannia Pharmaceuticals Ltd. (App. Br. 2.) 2 Quay, U.S. Patent Application Publication 2005/0090518 Al, published April 28, 2015. 3 Burczynski and Cote, U.S. Patent Application Publication 2008/0171072 Al, published July 17, 2008. 4 We understand parenteral administration to be administration by a route other than the gastrointestinal tract. 2 Appeal2017-004020 Application 14/152,000 Claim 1, Appellants' only independent claim, recites: A pharmaceutical composition for parenteral administration having an active substance and being provided in the form of a solution, the pharmaceutical composition compnsmg: i) apomorphine as the active substance; ii) a water miscible co-solvent; iii) an antioxidant; and iv) water; wherein a pH of the composition is greater than 4. (App. Br. 18, Claims App'x.) Findings of Fact Based on the Examiner's rejection, we make the following findings of fact, which are supported by a preponderance of the evidence. 1. Quay is directed to formulations of apomorphine, along with an apomorphine prodrug, for the treatment of Parkinson's disease. (See Quay abstract.) 2. Quay teaches a formulation for nasal administration that comprises apomorphine, propylene glycol, ascorbic acid, and water. (See Quay ,r 27 and accompanying table; Final Act. 3.) 3. Appellants' Specification includes propylene glycol as a water- miscible co-solvent within the scope of the invention. (See Spec. 3: 19-20.) 4. Appellants' Specification includes ascorbic acid as an anti- oxidant within the scope of the invention. (See Spec. 4:4--5.) 5. Quay does not teach that the apomorphine formulation has a pH greater than 4. (See Final Act. 4.) 3 Appeal2017-004020 Application 14/152,000 6. Burczynski is directed to formulations of apomorphine as ocular inserts that can be used to induce vomiting in dogs. (See Burczynski ,r,r 3 and 4.) 7. Burczynski provides a comparative example in which apomorphine was administered intravenously to patients in a solution buffered to pH 5.5 using a phosphate buffer in water for injection. (Burczynski ,r 56; see Final Act. 4.) 8. Burczynski teaches that apomorphine can be protected from oxidative degradation by formulating it with antioxidants, such as ascorbic acid, at "an acidic pH." (Burczynski ,r 38; see Final Act. 4.) Analysis Appellants claim a composition that comprises four elements: apomorphine, a water miscible co-solvent, an antioxidant, and water. Quay teaches a composition that comprises apomorphine, a water miscible co- solvent (propylene glycol), an antioxidant (ascorbic acid), and water. (See Quay ,r 27; Findings of Fact 1--4.) Quay does not disclose the pH of this composition. (See Finding of Fact 5.) Burczynski teaches a composition of apomorphine for intravenous delivery that uses a phosphate buffer to maintain a pH of 5.5. (See Burczynski ,r 38.) The Examiner determined that [ t ]he person of ordinary skill in the art would have been motivated to [ modify the composition of Quay with the pH taught in Burczynski] in order to achieve a pharmaceutical composition comprising apomorphine wherein the apomorphine 4 Appeal2017-004020 Application 14/152,000 did not degradate[5]. One of ordinary skill in the art would achieve the predictable result of combating degradation with an acidic pH level and addition of antioxidants. Therefore, the invention as a whole would be obvious to the person of ordinary skill in the art. (Final Act. 4.) Appellants argue that the Examiner's reason to modify the composition of Quay by increasing the pH to 5.5 to combat degradation is an error. (See App. Br. 11-12.) Appellants argue that the "less acidic pH of an apomorphine solution ... increases the risk of degradation of the apomorphine, unless the apomorphine solution for parenteral administration can be stabilized." (Reply Brief ("Reply Br.") 5; see App. Br. 11-12.) Similarly, Appellants argue that "[ s ]imply dissolving apomorphine in water buffered to a pH of 5.5 ... does not result in a pharmaceutical composition for parenteral administration, but, at best, in a control solution in which apomorphine immediately starts to decompose." (Reply Br. 9.) We are not persuaded by these arguments because Appellants fail to cite evidence in a timely manner showing that a higher pH, which is still acidic, would increase the risk of degradation. 6 Appellants do not direct us 5 Appellants discuss the word "degradate" in their Reply Brief. (See Reply Br. 4.) It is assumed that the word is a typographical error and is understood to mean "degrade" because of the use of the word "degradation" in the next sentence. 6 In their Reply Brief, Appellants present a picture that reportedly shows "aqueous apomorphine solutions at pH values of 3, 4, 5, 6, and 6.5, respectively, after storage." (See Reply Br. 14.) Appellants assert that "[a] discoloration ( darkening) over time is an indication of destabilization, wherein the darkening becomes more pronounced with increasing pH values." (Id.) We do not consider this evidence because it was presented to 5 Appeal2017-004020 Application 14/152,000 to evidence in support of their assertion that a range of 3 to 4 is more suitable than other acidic pH levels. Appellants' Specification states that parenteral subcutaneous injection of an active pharmaceutical ingredient (API) formulated in acidic conditions may lead to in situ precipitation and chemical degradation under physiological conditions and pH. Low pH value of the formulation, as well as potential precipitation and degradation of the drug under physiological conditions, may induce local subcutaneous site reactions as redness, etching, local indurations and nodules which are sore and troublesome. This is typically the case of apomorphine when administered in a subcutaneous (SC) infusion. (Spec. 1 :24--30.) The Specification discusses "low pH" and "physiological ... pH," but does not define either term or indicate that either excludes the pH of 5. 5 taught in Burczynski. Appellants argue that Quay teaches an "acidic solution," but the pH taught in Burczynski is also acidic. 7 (See App. us for the first time in the Reply Brief and we therefore lack the benefit of the Examiner's review. See 37 C.F.R. § 4I.41(b )(1) ("A reply brief shall not include any new or non-admitted amendment, or any new or non-admitted affidavit or other Evidence."). In addition, we note that none of Appellants' claims include a limitation regarding time or storage. Accordingly, even if we considered this evidence, it would not be persuasive to show that the claimed composition would not have been obvious. 7 The Examiner finds that "[a] pH of 1-7 is an acidic pH level." (Ans. 7.) Appellants argue that this statement is factually incorrect because a pH of 7 is not acidic. (See Reply Br. 8.) Nevertheless, all of the pH values at issue in regard to the prior art and the pH values encompassed by Appellants' claims up to pH 7 are in the acidic range. (See, e.g., Reply Br. 8 ("It is undisputed that a pH of, for example, 4.5 is an acidic pH.").) We disagree with Appellants' statement that "claim 1 does not recite an acidic pH, but a pH of greater than 4." (Reply Br. 15.) 6 Appeal2017-004020 Application 14/152,000 Br. 11 ("However, this is merely a description of what is suggested in Quay, which is the preparation of an acidic solution."); see also App. Br. 12 ("Quay is completely silent about stability issues of apomorphine solutions and simply accepts that acidic pH values must be chosen.").) Thus, we are not persuaded by Appellants' argument that the Examiner's reasoning is flawed. Instead, in light of the evidence properly presented to us, the Examiner's position is reasonable that it would have been obvious to use the pH of 5.5 taught in Burczynski with the ingredients taught in Quay to avoid degradation. Appellants raise a similar argument against the Examiner's reliance on Burczynski. According to Appellants, Burczynski teaches away from the claimed invention because it teaches that apomorphine is subject to oxidative degradation that can be prevented by acidic pH in a formulation. (See App. Br. 13, citing Burczynski ,r 38.) As noted above, a pH of greater than 4 can be an acidic pH. Thus, paragraph 3 8 of Burczynski does not teach away from the claimed composition. Appellants also argue that the recitation in the preamble of claim 1 of "parenteral administration" is not merely an intended use of the ingredients and pH recited in the claim, but instead indicates limitations of stability and storage. Specifically, Appellants argue that [a] skilled artisan understands that a pharmaceutical composition for parenteral administration must at least be stable enough to be shipped to the patient and stored for a few days prior to being administered. The in-situ preparation of the comparison solution in Burczynski et al would not be considered by a skilled artisan to correspond to a pharmaceutical composition for parenteral administration because the comparison solution is not suitable for being 7 Appeal2017-004020 Application 14/152,000 shipped or stored. As such, the apomorphine in the comparison solution is subject to degradation at the high pH level of the comparison solution. This is not a problem in Burczynski et al because the comparison solution therein is only needed to confirm that the ocular inserts are functioning as intended. (App. Br. 10-11.) Similarly, Appellants assert that "it is the combination of all recited components that provides for the required shelf-life and the resulting ability of the pharmaceutical composition for parenteral administration to be injected into a patient suffering from Parkinson's disease." (App. Br. 11.) We are not persuaded by this argument because Appellants' claim 1 does not recite any limitations on stability or the ability to be shipped and stored. (See Ans. 8.) Although Appellants argue that their Specification discusses increased stability of the claimed composition (see Reply Br. 13), these features are not recited in the claims and, thus, do not limit the claims. See E-Pass Techs., Inc. v. 3Com Corp., 343 F.3d 1364, 1369 (Fed. Cir. 2003) ( claims must be interpreted in view of the specification without importing limitations from the specification into the claims unnecessarily). Appellants fail to direct us to evidence in support of their assertion that one of ordinary skill in the art would have understood a specific degree of stability is necessarily required for parenteral administration. Appellants' claim 1 is not limited to a particular shelf-life. Instead, nothing in Appellants' claims precludes the formulation and immediate parenteral administration of the claimed compound. Appellants raise several arguments that refer to only one of the references cited by the Examiner. We are not persuaded by these arguments because the Examiner's rejection is based on the combination of Quay and 8 Appeal2017-004020 Application 14/152,000 Burczynski under 35 U.S.C. § 103, not on an anticipation of the claimed inventions by either reference. "Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). For example, Appellants argue that the solution described in paragraph 27 of Quay would have a pH of approximately 3.6. (See App. Br. 8.) Appellants argue further that the compositions of samples 1 and 2 of paragraphs 31 and 32 of Quay would also be acidic because of the large amount of lactic acid added. (See App. Br. 8.) Neither of these arguments are persuasive because the Examiner's rejection is not that the claimed invention is anticipated by Quay. Similarly, Appellants argue that Burczynski teaches a removable ocular insert from a formulation that does not contain a co-solvent or propylene glycol. (See App. Br. 10 and 13.) Quay teaches a composition of apomorphine and the ingredients recited in claim 1, including the co-solvent propylene glycol. Thus, these arguments do not address the Examiner's rejection. Appellants also argue that Quay teaches a nasal formulation, not a formulation for subcutaneous or intravenous administration. (See App. Br. 9.) According to Appellants, the physical properties of the nasal formulation are different from those for parenteral administration and "ingredients provided to allow for a delivery via a nasal delivery system may not interfere with the other ingredients." (App. Br. 9.) Again, this argument refers only to the teachings of Quay and does not address the Examiner's rejection that 9 Appeal2017-004020 Application 14/152,000 the claimed composition would have been obvious over a combination of the teachings of Quay and Burczynski. Appellants argue further that the formulation taught in Quay is not suitable for parenteral administration because it includes what Appellants report to be a "the highly toxic excipient benzalkonium chloride, which is an antiseptic substance suitable for topical administration only." (App. Br. 9-- 10.) In addition to being unsupported attorney argument, 8 even if Quay teaches that other components are present in the formulations, it nevertheless teaches the components recited in Appellants' claim 1. Appellants do not argue or present persuasive evidence showing that those of ordinary skill in the art would have considered Quay to teach that benzalkonium chloride is a necessary ingredient when formulating a composition of apomorphine. Appellants have not provided us with a reason to believe that removing the 8 The Examiner cites evidence showing that benzalkonium chloride was known to be used in parenteral formulations, refuting Appellants' assertion that benzalkonium chloride is too toxic. (See Ans. 10, citing Mehmood and Fahooq, OPEN SCIENCE JOURNAL OF PHARMACY AND PHARMACOLOGY 3: 19-- 27 (2015) at 24--25 ("Mehmood").) Appellants reply that although Mehmood teaches using benzalkonium chloride for parenteral suspensions, it also states that "[b ]enzalkonium chloride is used in ophthalmic dosage forms & not in injectable dosage forms." (See Reply Br. 18, quoting Mehmood 25.) We are not persuaded by Appellants' argument because claim 1 is not limited to administration by injection, but encompasses all routes of parenteral administration. Furthermore, Appellants' argument that Mehmood was not available when the application was filed is unpersuasive because Mehmood was not cited as prior art, but instead to rebut Appellants' assertion that one of ordinary skill in the art would have dismissed Quay because it teaches using benzalkonium chloride. (See Reply Br. 18.) 10 Appeal2017-004020 Application 14/152,000 benzalkonimn chloride from the formulation of Quay would affect any of the other components recited in paragraph 27. Appellants also argue that Quay is directed to treating a dopamine deficiency with apomorphine in conjunction with apomorphine prodrug, but that paragraph 27 of Quay is directed to a formulation of only apomorphine. (See App. Br. 9; see also App. Br. 12.) According to Appellants, the portion of Quay cited by the Examiner is not directed to the desired product providing the benefits sought by Quay. (See App. Br. 9.) This argument is not persuasive because Appellants' claim 1 is not directed to a specific effect of administering the claimed composition or a method of using it. Appellants' claim 1 is merely directed to the recited composition, which includes the ingredients taught in Quay. Furthermore, the recitation of other ingredients in Quay does not negate the teaching of the claimed ingredients because Appellants' claim 1 recites the transitional phrase "comprising," which allows for other elements. ( Contra Reply Br. 10 ("It is unclear how Appellant's choice of the transitional phrase 'comprising' has a bearing on what Quay can include in the nasal formulations suggested therein.")). Appellants argue that paragraph 25 of Quay teaches away from parenteral administration because it suggests that subcutaneous and continuous infusion require injections that risk infection, discomfort, and other adverse effects. (See App. Br. 13, citing Quay ,r 25.) Paragraph 25 does not mention parenteral administration. Accordingly, we disagree with Appellants that one of ordinary skill in the art would have been discouraged from using parenteral administration after reading Quay. See In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994) ("A reference may be said to teach away when a person of ordinary skill, upon reading the reference, would be 11 Appeal2017-004020 Application 14/152,000 discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant."). Appellants argue for the first time in their Reply Brief that there was a long-felt need in the art for a pharmaceutical composition that causes fewer or no side effects. (See Reply Br. 9.) Appellants do not explain why the argument could not have been presented earlier and do not show why there is good cause that it should be considered, given its belated filing. Accordingly, we do not consider the argument. See 3 7 C.F .R. § 41.41 (b )(2) ("Any argument raised in the reply brief which was not raised in the appeal brief, or is not responsive to an argument raised in the Examiner's answer, including any designated new ground of rejection, will not be considered by the Board for purposes of the present appeal, unless good cause is shown."). Appellants have not persuaded us that the Examiner erred in rejecting claim 1 as being obvious over Quay and Burczynski. Claim 2 Claim 2 recites: "The composition of claim 1, wherein an amount of the active substance is between about 10 to 70 mg/ml." (App. Br. 18, Claims App'x.) The Examiner cites to paragraph 52 of Burczynski for the teaching of a dose for parenteral administration of 0.08 mg/kg. (See Final Act. 4.) The Examiner determines that it is not inventive to discover dosing regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. (See Final Act. 5.) The Examiner also finds that the medical arts recognize that drug therapy may be optimized by designing regimens that account for the concentration of a drug by considering factors such as weight, age, gender, renal and hepatic status. (See Final Act. 5.) 12 Appeal2017-004020 Application 14/152,000 We agree with Appellants that the concentration range recited in claim 2 is not a dosage regime. (See App. Br. 14; Reply Br. 6-7.) But we are not persuaded by Appellants' argument that the claimed concentration allows for a dosage regime wherein the active substance can be administered over a shorter period of time due to a smaller injection volume. (See App. Br. 14.) Appellants argue: "A skilled artisan would not arrive at such a shorter period of time through routine experimentation because the compositions of Quay or Burczynski et al are not stable at high concentrations." (App. Br. 14--15.) Because claim 2 does not recite limitations regarding a period of time for administration, the ability to ship the composition, or an injectable volume, we are not persuaded by this argument. Claim 2 recites only an amount between about 10 to 70 mg/ml. Appellants do not argue or cite to evidence showing that it would not have been routine for those of ordinary skill in the art to have optimized the concentration of apomorphine in a composition for parenteral administration to the recited amount. 9 "[I]t is to be expected that a change in temperature, 9 Appellants include a sheet titled "Product Information" in an appendix to their Reply Brief and request that it be considered as showing the solubility of apomorphine for the purposes of rebutting the Examiner's findings regarding adding more drug to a formation. (See Reply Br. 3, citing Ans. 9.) Although Appellants argue that this particular sheet was not available until after the Appeal Brief was filed (see Reply Br. 3), apomorphine has been known since at least 1970. (See Quay ,r 23 ("Apomorphine, as a dopamine agonist, has been proposed as a therapy for Parkinson's disease since at least 1970 and as a therapy for 'on-off fluctuations since at least 1987.").) Thus, we are not persuaded that Appellants were not aware of its solubility until after they had filed their Appeal Brief. Because Appellants do not present an argument based on the relative solubility of apomorphine in their Appeal Brief, and the Examiner had previously rejected claim 2 based on the 13 Appeal2017-004020 Application 14/152,000 or in concentration, or in both, would be an unpatentable modification." In re Aller, 220 F.2d 454, 456 (CCPA 1955). Appellants do not direct us to evidence that the claimed concentration would have been critical, that is unexpected or different in kind and not merely in degree from the results of the prior art. Nor do Appellants direct us to evidence that obtaining the claimed concentration would not have been within the capabilities of one skilled in the art. See id. Accordingly, we are not persuaded that the Examiner erred in rejecting claim 2 as being obvious over Quay and Burczynski. Other Dependent Claims Appellants argue that the claims dependent on claim 1 include separately patentable subject matter, but fail to discuss any specific elements of the claims. (See App. Br. 16.) We are not persuaded that the Examiner erred in rejecting any of Appellants' dependent claims because of the lack of specific argument against the rejections. See 37 C.F.R. § 4I.37(c)(l)(iv) ("A statement which merely points out what a claim recites will not be considered an argument for separate patentability of the claim."). Conclusion Upon consideration of the record and for the reasons given, the rejection of claims 1-3, 5-7, 11-14, and 17 under 35 U.S.C. § 103(a) over Quay and Burczynski is sustained. Therefore, we affirm the decision of the Examiner. knowledge in the art to optimize drug concentration (see Final Act. 5), this evidence was presented too late for consideration. See 37 C.F.R. § 41.41 (b )(1 ). 14 Appeal2017-004020 Application 14/152,000 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136. AFFIRMED 15 Copy with citationCopy as parenthetical citation