HUNT, Terrence J.Download PDFPatent Trials and Appeals BoardMay 12, 202013427582 - (D) (P.T.A.B. May. 12, 2020) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE 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 APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 13/427,582 03/22/2012 Terrence J. HUNT 17859-CIP-CON (BOT) 7676 51957 7590 05/12/2020 ALLERGAN, INC. 2525 DUPONT DRIVE, T2-7H IRVINE, CA 92612-1599 EXAMINER LYONS, MARY M ART UNIT PAPER NUMBER 1645 NOTIFICATION DATE DELIVERY MODE 05/12/2020 ELECTRONIC 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. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): blake.morgan@allergan.com pair_allergan@firsttofile.com patents_ip@allergan.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte TERRENCE J. HUNT __________ Appeal 2019-003656 Application1 13/427,582 Technology Center 1600 __________ Before ERIC B. GRIMES, RACHEL H. TOWNSEND, and CYNTHIA M. HARDMAN, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a pharmaceutical composition, which claims have been rejected as anticipated and obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE Appellant’s Specification states that “pharmaceutical compositions comprising a protein active ingredient have been, or are currently being, developed. Unfortunately, a protein active ingredient can be very difficult to 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as Allergan, Inc. (Appeal Br. 3.) Appeal 2019-003656 Application 13/427,582 2 stabilize . . . resulting in a loss of protein and/or loss of protein activity during the formulation, reconstitution (if required) and storage of the pharmaceutical composition prior to use.” (Spec. ¶ 3.) In addition, Appellant’s Specification states: Clostridial toxins are large proteins having an average molecular weight of approximately 150 kDa, and are further complexed with non-toxin associated proteins that increase the size to approximately 300-900-kDa. The size of a Clostridial toxin complex makes it much more fragile and labile than smaller, less complex proteins, thereby compounding the formulation and handling difficulties if Clostridial toxin stability is to be maintained. (Id. ¶ 5.) It is also further noted that “despite their known stabilizing effects, significant drawbacks exist to the use of protein excipients, such as albumin or gelatin, in a pharmaceutical composition.” (Id. ¶ 4.) For example, “it is known that the possibility exists that the presence of an animal-derived protein excipients in a pharmaceutical composition can result in inadvertent incorporation of infectious elements into the pharmaceutical composition.” (Id.) Appellant’s invention relates to botulinum toxin, a clostridial toxin, in a pharmaceutical composition stabilized with a non-protein excipient. (Id. ¶¶ 10, 13.) Claims 20–25, 27–33, 41, and 43–46 are on appeal. Claim 20 is representative and reads as follows: 20. A pharmaceutical composition comprising: (a) a botulinum toxin, (b) a sugar excipient, and (c) a surfactant; wherein the botulinum toxin is not stabilized by a protein excipient, and wherein the sugar excipient is a monosaccharide, a disaccharide or a trisaccharide. Appeal 2019-003656 Application 13/427,582 3 (Appeal Br. 15.) The prior art relied upon by the Examiner is: Name Reference Date Johnson US 5,756,468 May 26, 1998 Donovan US 2004/0086532 A1 May 6, 2004 D. A. Parkins and U. T. Lashmar, The formulation of biopharmaceutical products, 3(4) PSIT 129–37 (2000) G. Atmaca, Antioxidant Effects of Sulfur-Containing Amino Acids, 45(5) Yonsei Medical Journal 776–88 (2004) The following grounds of rejection by the Examiner are before us on review: Claims 20, 22, 29, and 312 under 35 U.S.C. § 102(b) as anticipated by Donovan. Claims 20–25, 29–33, 41, 44, and 46 under 35 U.S.C. § 103(a) as unpatentable over Donovan and Parkins. Claims 28 and 43 under 35 U.S.C. § 103(a) as unpatentable over Donovan, Parkins, and Johnson. Claims 27, 28, 43, and 45 under 35 U.S.C. § 103(a) as unpatentable over Donovan, Parkins, and Atmaca. 2 Claims 34–40 were canceled by an Amendment filed July 5, 2018 after the Final Rejection. Thus, we do not refer to these canceled claims in stating the Examiner’s rejection of the claims made in the Final Action. Moreover, the cancellation of these claims renders moot the Examiner’s rejection of them on the ground of non-statutory double patenting. (Ans. 12.) Appeal 2019-003656 Application 13/427,582 4 DISCUSSION Anticipation We address claim 20, as Appellant does not separately argue the claims asserted to be anticipated (Appeal Br. 9–10). See 37 C.F.R. § 41.37(c)(1)(iv) (where multiple claims are rejected under a particular ground, and Appellant argues all claims as a group, “all claims subject to the ground of rejection stand or fall together”). The Examiner finds that Donovan teaches a pharmaceutical composition that includes a) botulinum toxins, b) a sugar that can be glucose, lactose and/or sucrose, and c) a surfactant, such as Tween 80. (Final Action 3 (citing Donovan claims 1, 4, and 20; ¶¶ 73, 131, 158, 184).) The Examiner further finds that “Donovan does not require a protein excipient for stabilization (e.g., [0033-0035]).” (Id.) Consequently, the Examiner concludes that Donovan anticipates claim 20. We agree with the Examiner’s findings and conclusion of anticipation. Donovan provides a list of “suitable excipients” “[t]o stabilize a neurotoxin” and that list includes, among other excipients, sugars (e.g., glucose, lactose, and sucrose), as well as surfactants (e.g., magnesium stearate, sodium stearate, and glycerol monostearate). (Donovan ¶ 131.) Donovan also teaches that more than one type of stabilizing excipient may be used in combination. (Id. (“The neurotoxin in a neurotoxin oral formulation can be mixed with excipients, bulking agents and stabilizing agents, and buffers to stabilize the neurotoxin during lyophilization or freeze drying.”).) Appeal 2019-003656 Application 13/427,582 5 Appellant does not dispute that Donovan teaches using sugars and surfactants in combination with botulinum toxin so as to be anticipating. Rather, Appellant argues the Examiner’s rejection is in error because “the toxin in Donovan’s formulation is stabilized by a protein excipient.” (Appeal Br. 9 (emphasis added).) Appellant arrives at this conclusion because (a) Donovan teaches using a diluted toxin produced from the Clostridial botulinum bacteria in solid form intended for long term use, which thus requires “a suitable stabilizing agent [be] present (Donovan, [36])” (id. at 10); (b) Donovan refers to obtaining botulinum toxin type A using the Schantz process and “incorporates” the article describing that process “by reference”3 (id.), and (c) Donovan provides examples of using commercially available botulinum toxin, which is stabilized with a protein which is added to an oral formulation with “additional pharmaceutical excipients that can be used to stabilize the toxin in the oral formulation matrix” (id. at 11). We do not agree with Appellant that Donovan requires the use of a protein to stabilize the botulinum toxin for use in its oral formulation. While the Examiner is correct that the claims are not limited to a particular concentration of botulinum toxin (Ans. 13), we agree with Appellant (Appeal Br. 10) that Donovan teaches the necessity of diluting the toxin for use in a pharmaceutical composition, which is what the claimed composition is, and that such dilution is known to “result [] in rapid detoxification of the toxin unless a suitable stabilizing agent is present.” 3 E. Schantz and E. Johnson, Properties and Use of Botulinum Toxin and Other Microbial Neurotoxins in Medicine, 56 Microbiological Reviews 80– 99 (1992). Appeal 2019-003656 Application 13/427,582 6 (Donovan ¶ 36.) However, we disagree with Appellant that Donovan teaches that stabilization of a dilute botulinum toxin to be used in a pharmaceutical composition must be achieved by use of a protein. First, we address Appellant’s reliance on the incorporation of Schantz in the Donovan disclosure. Even if Donovan incorporates the disclosure of Schantz by reference (Donovan ¶¶ 34, 194), Donovan does not limit the botulinum toxin to be used to one obtained by the Schantz process. Donovan merely teaches that such is a process by which one can obtain and purify botulinum toxin. (Id. ¶ 34.) Moreover, we agree with the Examiner that Schantz discloses that human serum albumin used in stabilizing botulinum toxin “presents potential problems.” See Schantz 81. In particular, Schantz teaches that “[a]lthough the commercial botulinum type A product is prepared in the presence of human serum albumin, the use of human serum albumin presents potential problems in that certain stable viral agents carried through from donors could contaminate the toxin.” (Id.) Furthermore, Schantz teaches that loss of toxicity when storing a lyophilized botulinum toxin stabilized with human albumin is significant at pH 7.3 (i.e., neutral pH) and “research” to develop a medium and conditions to overcome losses on drying was being conducted. (Id. at 83.) Consequently, Schantz itself provides one of ordinary skill in the art with motivation to find and use an alternative stabilizing compound. Furthermore, we agree with the Examiner (Ans. 13), that in describing known “stabilizing agents such as albumin and gelatin” (Donovan ¶ 36), Donovan was not limiting stabilization of botulinum toxin to only those agents, as evident by the use of the term “such as.” In fact, Donovan teaches that “[i]t has been discovered that a stabilized neurotoxin can comprise Appeal 2019-003656 Application 13/427,582 7 biologically active, non-aggregated neurotoxin complexed with at least one type of multivalent metal cation which has a val[e]ncy of +2 or more.” (Id. ¶ 132.) Donovan notes that “[a] preferred metal cation used to stabilize a botulinum toxin is Zn++ because the botulinum toxin[s] are known to be zinc endopeptidases.” (Id. ¶ 135.)4 Donovan describes how the “[t]he suitability of a metal cation for stabilizing neurotoxin can be determined” with a number of “stability indicating techniques” including “potency tests on neurotoxin lyophilized particles containing metal cations to determine the potency of the neurotoxin after lyophilization and for duration of release from microparticles.” (Id. ¶ 136.) Donovan further explains: In stabilized neurotoxin, the tendency of neurotoxin to aggregate within a microparticle during hydration in vivo and/or to lose biological activity or potency due to hydration or due to the process of forming a sustained release composition, or due to the chemical characteristics of a sustained release composition, is reduced. (Id.)5 The conditions for preparing such a stable toxin are described, including appropriate pH and suitable aqueous solvent and then lyophilizing to form particulates of stabilized neurotoxin. (Id. ¶¶ 144–149.) 4 We note that the Examiner relies on these cited paragraphs in the rejection. (See Final Action 3.) 5 Donovan also notes that “[i]t is known that a significant water content of lyophilized tetanus toxoid can cause solid phase aggregation and inactivation of the toxoid once encapsulated within microspheres.” (Id. ¶ 168.) Donovan explains that the manufacturing process for BOTOX® results in a freeze dried botulinum toxin type A complex which has a moisture content of less than about 3%, at which moisture level nominal solid phase aggregation can be expected. (Id.) Appeal 2019-003656 Application 13/427,582 8 Consequently, we conclude that Donovan’s references to using a stabilized neurotoxin do not require that the neurotoxin be stabilized with a protein excipient. All that Donovan requires is stabilization of a neurotoxin, which it teaches may be accomplished with a variety of specifically identified suitable excipient compounds, which, as the Examiner found, include the sugars: glucose, lactose, and sucrose, and the surfactants: magnesium stearate, sodium stearate, glycerol monostearate. (Id. ¶ 131.)6 “[A] reference can anticipate . . . if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination.” Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381 (Fed. Cir. 2015). Although anticipation does not require a reference discuss “the actual combination to anticipate,” when it does not, it must teach “that the disclosed components or functionalities may be combined.” Blue Calypso, LLC v. Groupon, Inc., 815 F.3d 1331, 1344 (Fed. Cir. 2016). We conclude such is the case here. The list of suitable excipients is small, and Donovan teaches that more than one stabilizing component can be used together. (Id. ¶ 131; see also ¶ 132 (noting the use of “at least one type of multivalent metal cation” with a valency of +2 or 6 Although not necessary to our conclusion, we agree with the Examiner (Ans. 17), that US 2003/0138437, published July 24, 2003, assigned to Allergan, Inc. (“Hunt”), which was published nearly one year earlier than Donovan, also assigned to Allergan, Inc., teaches an art-recognized need to make stabilized botulinum toxin formulations that are free of proteins like albumin. (Hunt ¶¶ 43, 81–82.) Hunt describes a protein-free stabilizing agent for use with botulinum toxin. (Id. ¶¶ 82, 111, 113.) Thus, Hunt is further support that one of ordinary skill in the art at the time the invention was made would not have interpreted Donovan to require stabilization of botulinum toxin with a protein. Appeal 2019-003656 Application 13/427,582 9 more for stabilizing a neurotoxin).) Moreover, when the number of categories and components in a reference is not large, such as the case here, the combination claimed is clearly identifiable. See Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1361–62 (Fed. Cir. 2012). Thus, we affirm the Examiner’s rejection of claims 20, 22, 29, and 31 under 35 U.S.C. § 102(b) as anticipated by Donovan. Obviousness For all of the obviousness rejections, the Examiner maintains the position that Donovan teaches a botulinum composition that includes a sugar and a surfactant and further relies on additional references for the obviousness of selecting particular surfactants (poloxamer 188) and sugars (trehalose), recited in dependent claims and independent claim 41, as well as additionally required ingredients, like specific buffers and antioxidants. (See, e.g., Final Action 6, 10, 12.) Appellant contests these rejections because of Appellant’s basic disagreement with the Examiner that Donovan requires a protein excipient to stabilize the botulinum toxin. (Appeal Br. 11–12 (addressing the rejection that additionally relies on Parkins), 13 (addressing both the rejection that additionally relies on Johnson and the rejection that relies on Atmaca).) Appellant then further argues that the additional references do not cure that deficiency and the references do not teach or suggest all the elements of the claims. We do not find Appellant’s arguments persuasive because we agree with the Examiner that Donovan teaches a botulinum toxin composition that includes a sugar and a surfactant, and does not require a protein excipient to stabilize the botulinum toxin. Appeal 2019-003656 Application 13/427,582 10 Thus, we affirm the Examiner’s rejection of: claims 20–25, 29–33, 41, 44, and 46 under 35 U.S.C. § 103(a) as unpatentable over Donovan and Parkins, claims 28 and 43 under 35 U.S.C. § 103(a) as unpatentable over Donovan, Parkins, and Johnson, and claims 27, 28, 43, and 45 under 35 U.S.C. § 103(a) as unpatentable over Donovan, Parkins, and Atmaca. DECISION SUMMARY Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 20, 22, 29, 31 102(b) Donovan 20, 22, 29, 31 20–25, 29– 33, 41, 44, 46 103(a) Donovan, Parkins 20–25, 29– 33, 41, 44, 46 28, 43 103(a) Donovan, Parkins, Johnson 28, 43 27, 28, 43, 45 103(a) Donovan, Parkins, Atmaca 27, 28, 43, 45 Overall Outcome 20–25, 27– 33, 41, 43– 46 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv). Appeal 2019-003656 Application 13/427,582 11 AFFIRMED Copy with citationCopy as parenthetical citation