Ex Parte GreveDownload PDFPatent Trial and Appeal BoardDec 14, 201713062388 (P.T.A.B. Dec. 14, 2017) 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. 13/062,388 07/05/2011 Harald Greve 78-10866 3686 77741 7590 12/18/2017 Rrannnn Sowers; Rr rYarraft PP EXAMINER 47 South Meridian Street KIM, JENNIFER M Suite 400 Indianapolis, IN 46204 ART UNIT PAPER NUMBER 1628 NOTIFICATION DATE DELIVERY MODE 12/18/2017 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): docket @ bscattorney s. com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte HARALD GREVE Appeal 2017-001169 Application 13/062,388 Technology Center 1600 Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and DAVID COTTA, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35U.S.C. § 134 involving claims to a combination therapeutic for the prophylactic or therapeutic treatment of respiratory disorders. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Statement of the Case Background “[Bjoth for bronchial asthma and for COPD [chronic obstructive pulmonary disease] — in addition to a basic therapy with bronchodilators — 1 Appellant identifies the Real Party in Interest as Maria Clementine Martin Klosterfrau Vertriebsgesellschaft mbH (see App. Br. 3). Appeal 2017-001169 Application 13/062,388 topical or local, in particular inhalative or inhalable, corticosteroids are [also] used” (Spec. 4:28—31). The prior art describes “a combination therapy with, firstly, orally administered terpene compounds, in particular 1, 8-cineol or menthol, and, secondly, likewise systemic, in particular orally administe[re]d corticosteroids for the anti-inflammatory treatment of chronic bronchial asthma” (Spec. 8:16—20). The Specification states “[hjowever, the administration of systemic corticosteroids is associated with serious side-effects.” (Spec. 8:24—26) and “[a]s a consequence, the prior-art treatment methods of bronchopulmonary disorders or respiratory disorders often do not give the desired therapeutic result, or only with unwanted side-effects” (Spec. 9:1—4). The Claims Claims 16, 20-23, 26, 27, 31, 32, 41, and 42 are on appeal. Independent claim 16 is representative and reads as follows: 16. A combination therapeutic for the prophylactic or therapeutic treatment of respiratory disorders selected from bronchopulmonary disorders to reduce the dose or to enhance the activity of a topically administrable inhalative respiratory therapeutic in the prophylactic or therapeutic treatment of the respiratory disorders, wherein the combination therapeutic is in the form of a kit and comprises: (a) at least one systemically administrable monoterpene, wherein the monoterpene is 1,8-cineol and wherein the monoterpene is present in the form of an oral enteric preparation which dissolves in the small intestine, and (b) at least one topically administrable respiratory therapeutic, wherein the topically administrable respiratory therapeutic is an inhalative respiratory therapeutic selected from the group consisting of (i) corticosteroids; (ii) sympathomimetics; and 2 Appeal 2017-001169 Application 13/062,388 mixtures as well as combinations thereof; and wherein the bronchopulmonary disorder is bronchial asthma, bronchitis or chronic obstructive pulmonary disorder (COPD). The Issue The Examiner rejected claims 16, 20-23, 26, 27, 31, 32, 41, and 42 under 35 U.S.C. § 103(a) as obvious over Juergens,2 Britto,3 and Fischli4 (Final Act. 2-4). The Examiner finds “Juergens teaches that because of the synergistic effect, a combination treatment comprising 1,8 -cineol and the conventional corticosteroids such as beclomethasone is recommended” (Final Act. 2—3). The Examiner finds the Juergens teaches 1,8 —cineol administration “in the form of gastric juice-resistant capsules with a dose unit of lOOmg/capsule” (id. at 3). The Examiner acknowledges Juergens does not teach “beclomethasone in inhalation form”; “a kit”; and “employment of enteric coating” (Final Act. 3). The Examiner finds Fischli teaches that for “preparations which are resistant to gastric fluids it is necessary to apply a gastric fluid-resistant (enteric) coating” (id.). The Examiner finds Britto teaches “a metered dose inhaler comprising beclomethasone dipropionate optionally in combination with one or more other pharmacologically active agents” (id.). The Examiner finds it obvious to “modify the combination therapeutics of Juergens and employ beclomethasone in inhalation form 2 Juergens, U., US 5,889,049, issued Mar. 30, 1999. 3 Britto et al., US 6,511,653 Bl, issued Jan. 28, 2003 4 Fischli et al., US 4,929,741, issued May 29, 1990. 3 Appeal 2017-001169 Application 13/062,388 because beclomethasone in an inhalation aerosol form is readily available in the market and has been accepted by the medical community” (Final Act. 4). The issues with respect to this rejection are: (i) Does the evidence of record support the Examiner’s conclusion that Juergens, Britto, and Fischli render claim 16 obvious? (ii) If so, has Appellant presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness? Findings of Fact 1. Juergens teaches “ 1,8-cineol is suitable for treating inflammatory allergic and/or inflammatory bronchopulmonary diseases requiring steroid treatment and exacerbated by infection” (Juergens 2:48— 51). 2. Juergens teaches: “Because of the synergistic effect, a combination treatment comprising 1,8-cineol and the conventional corticosteroids prednisone, prednisolone, fluocortolone, beclomethasone, budesonide or fhmisolide is recommended” (Juergens 2:66 to 3:2; emphasis added). 3. Juergens teaches the 1,8 cineol “dosage of 200 mg/day to 900 mg/day (by preference 600 mg/day) can be administered in the form of gastric juice-resistant capsules with a dose unit of 100 mg/capsule” (Juergens 3:13—15). 4. Fischli teaches: “For the preparation of pharmaceutical preparations which are resistant to gastric fluids it is necessary to apply a gastric fluid-resistant (enteric) coating which can consist of, for example, 4 Appeal 2017-001169 Application 13/062,388 hydroxypropylmethylcellulose phthalate or other suitable material, as those skilled in the art will understand” (Fischli 11:57—62). 5. Britto teaches “[bjeclomethasone dipropionate in aerosol form, has been accepted by the medical community as useful in the treatment of asthma and is marketed under the trademarks ‘Beclovent’, ‘Becotide’, and ‘Beconase’” (Britto 2:33—36). 6. Britto teaches “beclomethasone dipropionate (or a physiologically acceptable solvate thereof) in combination with one or more other pharmacologically active agents. Such medicaments may be selected from any suitable drug useful in inhalation therapy” (Britto 3:5—9). Principles of Law “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Analysis We adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Final Act. 2-4; FF 1—6) and agree that the claims are obvious over Juergens, Fischli, and Britto. We address Appellant’s arguments below. Prima Facie Obviousness Appellant contends the Juergens patent teaches administering both components by mouth (systemically) whereas the current application requires the monoterpene to be administered systemically, whereas the respiratory therapeutic is required to be administered topically, the very distinction noted by Prof. Dr. Juergens. As a result, 5 Appeal 2017-001169 Application 13/062,388 Applicant’s combined therapeutic requires a method of administration that is different from that taught by Juergens. (App. Br. 17-18). We find this argument unpersuasive because it fails to address the teachings of Juergens, Fischli, and Britto in combination. Juergens teaches treatment of bronchopulmonary disease with 1,8-cineol (FF 1) in oral enteric form (FF 3) in synergistic combination with corticosteroids including beclomethasone (FF 2). While Juergens does not teach an aerosol inhalation form of a corticosteroid, as acknowledged by the Examiner (see Final Act. 3), Britto teaches that aerosol inhalation forms of the corticosteroid beclomethasone were well known (FF 5) and useful in combination therapy with other agents (FF 6). It is this combination of Juergens and Britto that renders claim 16 obvious, not the teachings of Juergens alone. “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). Appellant cites the Juergens5 Declaration “to illustrate the principle that there are differences in the effects obtained for systemic and topical administration of medicants” and contends “the Examiner dismissed Dr. Juergens’ opinion supported by Attachment A, and maintained what appears to be an unspoken and unsupported belief in the equivalence in the two modes of medicant administration” (App. Br. 20). In the cited portion, Dr. Juergens stated 5 Declaration of Dr. Prof. Uwe R. Juergens, dated Feb. 5, 2014. 6 Appeal 2017-001169 Application 13/062,388 it was not at all foreseeable or predictable on the basis of the teaching of my patent, the other cited art, or their combination that the “exhalation” of the systemically applied monoterpene in the alveolar and/or bronchial epithelium would be effective enough to provide concentrations sufficient to allow the interaction of 1,8-cineol with the topically administered respiratory therapeutic within the respiratory system such that the combination can act together to advantageously impact the respiratory system in a synergistic manner. (Juergens Decl. 111). We have considered the Juergens Declaration, and recognize Dr. Juergens expertise and familiarity with the technology, but find it unpersuasive of nonobviousness when weighted with the evidence presented in Juergens and Britto. Dr. Juergens points out that topical and systemic treatments with compounds may provide different results (Juergens Decl. 19) and specifically contends that he considered only systemic treatments and did not consider inhalation treatment with corticosteroids (Juergens Decl. 110). However, the issue is not whether systemic and oral administration modes are equivalent, but rather whether the ordinary artisan would have had reason to use inhalation administration routes as disclosed by Britto in the combination treatment method of Juergens. Dr. Juergens provides no experimental or other evidence supporting the position that known treatment options such as the aerosol forms of beclomethasone of Britto, specifically “accepted by the medical community as useful in the treatment of asthma” (FF 5) and therefore demonstrated to have biologic effects on the specific respiratory target tissue in the current claim 16, would not be expected to provide benefits when used in combination with other therapeutic agents 7 Appeal 2017-001169 Application 13/062,388 such as 1,8-cineol (FF 1), which were known to be useful in combination with corticosteroids, albeit in systemic form (FF 2). Dr. Juergens simply states his expert opinion. However, “[t]he Board has broad discretion as to the weight to give to declarations offered in the course of prosecution . . . [and] the Board is entitled to weigh the declarations and conclude that the lack of factual corroboration warrants discounting the opinions expressed in the declarations.” In re Am. Acad. Science Tech Ctr., 367 F.3d 1359, 1368 (Fed. Cir. 2004). We recognize, but find unpersuasive, Appellant’s contention that “the Examiner dismissed Dr. Juergens’ opinion supported by Attachment A, and maintained what appears to be an unspoken and unsupported belief in the equivalence in the two modes of medicant administration” (App. Br. 20).6 In fact, the Examiner addressed this issue (see Ans. 3). Moreover, Appellant has provided evidence that supports the Examiner’s obviousness position regarding the use of inhaled and system corticosteroids. Attachment B to the Juergens Declaration, the prior art document by Havill et al.,7 states “[tjopical corticosteroids are generally preferred to systemic steroids because of enhanced control of local disease and a potential reduction in adverse effects.” (Juergens Deck Attachment B, 1). Havill et al. further notes “inhaled steroids have a more favourable side effect profile than systemic steroids” {id. at 3). Similarly, Attachment C, the prior art 6 We note that Appellant’s request for a § 104(d)(2) affidavit or declaration by the Examiner is clearly inappropriate because the Examiner is relying not on personal knowledge but on the teachings of the cited references. 7 Havill et al., Poorly Recognised Adverse Effects of Inhaled Corticosteroids, http://www.medsafe.govt.nz/profs/puarticles/2.htm (July 1998). 8 Appeal 2017-001169 Application 13/062,388 document by Barnes,8 states “inhaled corticosteroids have become first-line therapy and by far the most effective anti-inflammatory treatment” (id. at Attachment C, 1). Attachment D, a post-filing date reference by Roberts et al.,9 states “Beclomethasone dipropionate (BDP)... is a glucocorticoid administered by inhalation to treat asthma” (id. at Attachment D, 1) and states “[ijnhaled glucocorticoids are the mainstay treatment of asthma” (id. at Attachment D, 6). Thus, in addition to Britto’s direct teaching to treat asthma with inhaled beclomethasone (FF 5) in combination with other drugs (FF 6), the references cited by Appellant provide specific reasons known and available to the ordinary artisan that would have led to the use of inhaled steroids due to their “enhanced control of local disease” and “more favourable side effect profile” (Juergens Decl. Attachment B 1, 3) and because they are “by far the most effective anti-inflammatory treatment” (id. at Attachment C, 1). As we balance Dr. Juergens’ opinion Declaration against the evidence cited by the Examiner and in the attachments, we remain persuaded that the ordinary artisan would have had reason to modify the 1,8-cineol and beclomethasone treatment taught by Juergens to use inhaled beclomethasone as taught by Britto for the reasons recited above. We recognize, but find unpersuasive, Appellant’s arguments that “[w]e don’t fully understand, in the case of Prof. Dr. Juergen’s fully 8 Barnes, P., How corticosteroids control inflammation: Quintiles Prize Lecture 2005, 148 Br. J. Pharmacol. 245—254 (2006). 9 Roberts et al., Metabolism of Beclomethasone Diproprionate by Cytochrome P450 3A Enzymes, 345 J. Pharmacol. Exp. Ther. 308—316 (2013). 9 Appeal 2017-001169 Application 13/062,388 systemically administered combination, whether the interaction of the two components occurs in the liver, the lungs, or elsewhere” (App. Br. 25). There is no evidence that the two components, the corticosteroid and the 1,8- cineol, interact directly at all in either the Specification or the cited art, and this is not a limitation of claim 16. See In re Self, 671 F.2d 1344, 1348 (CCPA 1982) (“[AJppellanf s arguments fail from the outset because . . . they are not based on limitations appearing in the claims.”) For purposes of a therapeutic treatment, once the combination of agents has been suggested as efficacious for a particular condition, as evidenced here for 1,8-cineol and beclomethasone for bronchopulmonary diseases by Juergens, the specific mode of action would only matter if evidence was presented that the preferred mode of administration failed to achieve the therapeutic effect. Here, Britto, and Attachments B and C to the Juergens Declaration all evidence that inhaled beclomethasone results in the desired therapeutic effect (FF 5; Juergens Decl Attachment B, 1 and Attachment C, 1), rendering Appellant’s argument regarding the mode of action less relevant to the ultimate determination of obviousness. We recognized, but find unpersuasive, Appellant’s contention that “the proposed modification of the therapeutic taught by Prof. Dr. Juergens would have been expected to render the modified therapeutic unsatisfactory for its intended purpose” (App. Br. 32, citing Juergens Decl. 8 and Greve Decl. 11). No specific evidence supporting these opinion findings was presented, and Britto specifically evidences that beclomethasone aerosol “has been accepted by the medical community as useful in the treatment of asthma” (FF 5) along with the teachings in Attachments B and C that 10 Appeal 2017-001169 Application 13/062,388 “[tjopical corticosteroids are generally preferred to systemic steroids” (Juergens Decl. Attachment B, 1) and that “inhaled corticosteroids have become first-line therapy and by far the most effective anti-inflammatory treatment” (id. at Attachment C, 1). Thus, the balance of the evidence supports the Examiner’s position that the skilled artisan would reasonable have expected that improving the method of Juergens by using the inhaled beclomethasone of Britto would be successful. “Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success.'1'’ In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (citation omitted). We recognize, but find unpersuasive, Appellant’s contention that “the Examiner has only posited that one skilled in the art would make the proposed combination because the components were commercially available, whereas Applicant has provided the reasoned opinion of the inventor on the cited patent to refute the Examiner’s position” (App. Br. 35). While we have already provided reasons why we find the combination obvious and predictable based on the combined teachings of Juergens, Fischli, and Britto (FF 1—6), we note that the evidence presented by Appellant regarding the knowledge of a person of ordinary skill also supports a finding of obviousness based on the knowledge that “[tjopical corticosteroids are generally preferred to systemic steroids” (Juergens Decl., Attachment B, 1) and that “inhaled corticosteroids have become first-line therapy and by far the most effective anti-inflammatory treatment” (id. at Attachment C, 1). 11 Appeal 2017-001169 Application 13/062,388 We also do not find that the Examiner relied upon inherency, as argued by Appellant (see, e.g., Reply Br. 16), but rather on the express teachings of the prior art (FF 1—6) and the knowledge of the ordinary artisan. Unexpected Results Appellant states “[pjlease note paragraphs 8 and 10 of Dr. Greve’s Declaration where greater than expected results are described, and the presence of an unexpected antioxidant property is discussed” (App. Br. 28). Appellant cites the Greve Declaration,10 which states “administration of 1,8- cineol may allow the topical or inhalative respiratory therapeutic in question to be used for the first time for certain respiratory disorders or for certain stages of the respiratory disorders,” including COPD, where its lack of sensitivity had previously precluded its use (Greve Decl. 1 8). Appellant also cites the Greve Declaration’s statement that a “further unexpected and unpredictable result of the combined systemic and topical administration of medicants according to claims [sic] 16 and new claims 40-42 was the antioxidative and anti-inflammatory effect of 1,8-cineol and its ability to moderate the oxidative effect resulting from the administration of beclometasone” (Greve Decl. 110). The Greve Declaration cites the Specification’s teaching that for the first time, the present study now shows that the strong inhibition of the production of O2" radicals by therapeutic concentrations of 1,8-cineol in combination with beclometasone can be demonstrated and provides an advantage which cannot be mediated in an isolated manner by the inhalative steroid alone. This is not a purely additive effect but the mediation of the effect of 1,8-cineol on the combination of 1,8-cineol and 10 Declaration of Dr. Harald Greve, dated Feb. 5, 2014. 12 Appeal 2017-001169 Application 13/062,388 beclometasone, without it being possible to detect an independent antioxidative effect of beclometasone. (Spec. 62:15 to 63:5). We have considered the evidence in the Specification and the Greve Declaration, but find the evidence, considered as a whole with the prima facie case of obviousness, does not support a finding of non-obviousness. In particular, we note that the Specification lacks a comparison with the closest prior art of Juergens, and fails to demonstrate any unexpected result for the inhaled form of a corticosteroid such as beclomethasone combined with 1,8-cineol that is compared to Juergens treatment with systemic corticosteroids and 1,8-cineol (see Juergens, Table II). See In re Baxter TravenolLabs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.”). Indeed, Appellant essentially admits that no such testing was performed when stating “had Applicant relied on comparative testing, it would have been helpful for the Examiner to cite where that occurred” (Reply Br. 7). In addition, Appellant has provided only opinion evidence in either the Greve Decl. or Juergens Deck that the improved treatment would not have been the expected result. Given the teaching by Juergens that 1,8- cineol is synergistic with corticosteroids such as beclomethasone (FF 2) and the teaching of Britto that inhaled beclomethasone was medically accepted and combinable with other agents (FF 5—6), and the evidence of Attachment B that the ordinary artisan would have known inhaled corticosteroids were preferred over systemic treatments for enhanced control of local disease and 13 Appeal 2017-001169 Application 13/062,388 reduction in side effects (Juergens Decl. Attachment B, 1), improved treatment using inhaled beclomethasone appears to be the expected result, rather than an unexpected result. See In re Skoner, 517 F.2d 947, 950 (CCPA 1975) (“Expected beneficial results are evidence of obviousness of a claimed invention. Just as unexpected beneficial results are evidence of unobviousness”). To the extent that Dr. Greve contends the result is unexpected based on his personal assessment, “an affidavit by an applicant or co-applicant as to the advantages of his invention is less persuasive than one made by a disinterested person.” In re Bulina, 362 F.2d 555, 559 (CCPA 1966). We consider the evidence, but we balance it with the other teachings of record. We recognize, but find unpersuasive, Appellant’s contentions that the “unexpected results derived from Applicant’s combination therapy include, but are not limited to: unexpectedly providing a treatment for COPD, demonstrating both the presence of an unexpected property (i.e., antioxidant properties and consistent therapeutic effects), and the absence of an expected property (i.e., side effects)” (App. Br. 31). Appellant provides no evidence that the treatment works for COPD in patients, with the only clinical results being drawn to “persistent bronchial asthma” (see Spec. 52, example 2). Thus, there is no evidence of unexpected results for COPD patients. Moreover, the claims are not commensurate in scope with this result because the claims encompass treatment of bronchial asthma and bronchitis as well as COPD. Unexpected results must be “commensurate in scope with the degree of protection sought 14 Appeal 2017-001169 Application 13/062,388 by the claimed subject matter.” In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). We find the “antioxidant” property argument unpersuasive of unexpected results because, as discussed above, no comparison with the closest prior art was performed. Indeed, the experiments performed in the Specification showing antioxidant activity (see, e.g., Spec. 62, Table 4) were performed by in vitro treatment of cells in culture, which more closely mimics systemic administration rather than inhaled administration because just as systemically administered drug is delivered in a solution to every cell, so too did the experiment incubate the cells with “different concentrations of beclomethasone” in solution form, rather than aerosol (see Spec. 60:6—10). Therefore, this result also fails to evidence unexpected results for the inhaled form of beclomethasone relative to the systemic form. Lastly, reduction in side effects is clearly an expected result of topical administration, as expressly explained in Attachment B that “[tjopical corticosteroids are generally preferred to systemic steroids because of enhanced control of local disease and a potential reduction in adverse effects.” (Juergens Decl. Attachment B, 1). We recognize, but find unpersuasive, Appellant’s reliance on Attachment D (see, e.g., Reply Br. 9). However, claim 16 is not drawn to a specific mode of action of beclomethasone, but rather to a specific mode of administration, inhaled. Attachment D, a post-filing date reference, provides no specific evidence regarding any unexpected results for the combination of 1,8-cineol and beclomethasone. We find Appellant’s arguments regarding the difference in the action of other drugs in inhaled versus systemic form 15 Appeal 2017-001169 Application 13/062,388 such as insulin (see, e.g., Reply Br. 9) particularly irrelevant given the express suggestion by Britto to administer beclomethasone in inhaled form (FF 5). We therefore conclude that the asserted results, when properly evaluated and weighted with the prima facie case of obviousness, does not result in determining that the claims are nonobvious. Conclusion of Law (i) The evidence of record supports the Examiner’s conclusion that Juergens, Britto, and Fischli render claim 16 obvious. (ii) Appellant has not presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness. SUMMARY In summary, we affirm the rejection of claim 16 under 35 U.S.C. § 103(a) as obvious over Juergens, Britto, and Fischli. Claims 20—23, 26, 27, 31, 32, 41, and 42 fall with claim 16. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 16 Copy with citationCopy as parenthetical citation