RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY et al.

Patent Trials and Appeals BoardMar 2, 2021

2020004190 (P.T.A.B. Mar. 2, 2021)

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. 16/053,537 08/02/2018 Edmond J. LaVoie 00535.013US6 3997 53137 7590 03/02/2021 VIKSNINS HARRIS PADYS MALEN LLP 7851 Metro Parkway Suite 325 Bloomington, MN 55425 EXAMINER O DELL, DAVID K ART UNIT PAPER NUMBER 1625 NOTIFICATION DATE DELIVERY MODE 03/02/2021 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): docketing@vhpmlaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte EDMOND J. LAVOIE, AJIT PARHI, DANIEL S. PILCH, YONGZHENG ZHANG, and MALVIKA KAUL Appeal 2020-004190 Application 16/053,537 Technology Center 1600 Before ERIC B. GRIMES, FRANCISCO C. PRATS, and DEVON ZASTROW NEWMAN, Administrative Patent Judges. NEWMAN, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claim 1. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 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 “Rutgers, The State University of New Jersey.” Appeal Br. 2. Herein, we refer to the Appeal Brief filed February 2, 2020 (“Appeal Br.”), the Examiner’s Answer filed March 18, 2020, (“Ans.”), and the Reply Brief filed May 15, 2020 (“Reply Br.”). Appeal 2020-004190 Application 16/053,537 2 STATEMENT OF THE CASE The emergence of Multidrug Resistant (MDR) bacterial pathogens (e.g. methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii-calcoaceticus complex (ABC), etc.) has increased concerns as to the adequacy of current antimicrobials and pathogen treatment methods. The lethality of such pathogens, particularly MRSA, has often led to treatment methods that are experimental or would otherwise normally be avoided in standard clinical practice. . . . The growing threat from MDR pathogens highlights a critical need for additional antimicrobials. In this connection, there is a pressing need for new antibiotics that exhibit novel mechanisms of action or that are able to circumvent known resistance pathways. Spec. 1:12–22. The Specification discloses “antibiotic compounds that are highly solu[ble] and that can be formulated for administration as antibiotic agents.” Id. at 2:9–10. CLAIMED SUBJECT MATTER Claim 1, directed to a chemical compound, is on appeal2 and is reproduced below: 1. The compound: Appeal Br. 13 (Claims App.). 2 Appellant addresses the status of claims 2 and 3 at Appeal Br. 4. As those claims are not before us on appeal, we take no position on the status or patentability of either claim. Appeal 2020-004190 Application 16/053,537 3 REFERENCES The prior art relied upon by the Examiner is: Name Reference Date David Brown et al. “Brown” WO 2007/107758 A1 Sept. 27, 2007 David J. Haydon et al. “Haydon”3 53: J. Med. Chem., 3927– 36 (2010) April 28, 2010 REJECTION Claim 1 is rejected under pre-AIA 35 U.S.C. § 103(a) as being obvious over Brown and Haydon. Answer 3–4. OPINION A. Issues The Examiner has rejected claim 1 as obvious based on Brown and Haydon. Id. The Examiner finds that Brown and Haydon teach three prior art compounds, described and reproduced in the chart below, with the compound of claim 1 provided for comparison: 3 Creating an Antibacterial with in Vivo Efficacy: Synthesis and Characterization of Potent Inhibitors of the Bacterial Cell Division Protein FtsZ with Improved Pharmaceutical Properties, 53: J. MED. CHEM., 3927– 36 (2010). Appeal 2020-004190 Application 16/053,537 4 Compound as identified in Brown Compound as identified in Haydon Structure 139 2 217 8e 218 8j Compound of claim 1 Appeal 2020-004190 Application 16/053,537 5 Compound 139 of Brown (“Brown 139/Haydon 2”) differs from the claimed compound in that it has a 6 position chlorine where the claimed compound has a trifluoride (CF3). Ans. 4. Compound 217 (“Brown 217/Haydon 8e”) has a benzothiazole group instead of a thiazolo[5,4- b]pyridine ring. Id. at 4–5. Compound 218 (“Brown 218/Haydon 8j”) also has a benzothiazole group instead of a thiazolo[5,4-b]pyridine ring as well as a 6 position chlorine where the claimed compound has a trifluoride (CF3). Id. at 5. Issue The Examiner finds that Brown identified compounds 139, 217, and 218 as “in the A group of most potent compounds” based on their antibacterial activity in a liquid media test. Id. at 5; Brown at 161–2. The Examiner finds that Haydon explored the structure-activity relationship (SAR) of compounds Brown 139/Haydon 2 and Brown 218/Haydon 8j in a murine model of staphylococcal infection. Ans. 5. The Examiner finds that Haydon disclosed that compound Brown 139/Haydon 2 was effective against infection in multiple administration methods while Brown 218/Haydon 8j was effective in only the highest potency administration (intraperitoneal). Ans. 5–6. The Examiner finds Haydon discloses that 5-substituted-1,3-benzothiazol-2-ylmethoxy compounds such as Brown 218/Haydon 8j bound to plasma too tightly to be further considered for drug development purposes (meaning the drug was not pharmacologically active, as it was bound to plasma proteins). Id. The Examiner finds that Haydon disclosed: Appeal 2020-004190 Application 16/053,537 6 Replacing the benzothiazole substituent with a thiazolopyridine [as in Brown 139/Haydon 2] reduced the antibacterial activity but also reduced the plasma protein binding. Furthermore, the metabolic stability of the thiazolopyridine was improved compared to the henzothiazole, resulting in an approximately 15-fold reduction in clearance following intravenous administration in the mouse. Ans. 7 (quoting Haydon 3932–3). The Examiner finds that the improved overall performance of compound Brown 139/Haydon 2, which Haydon attributed to the thiazolopyridine substitution, would have motivated the skilled artisan interested in developing antibacterial compounds to modify compounds having a benzothiazole group to substitute benzothiazole group with thiazolopyridine. Id. at 6–7. Specifically, the Examiner finds the artisan would have been motivated to modify compound Brown 217/Haydon 8e “by replacing the benzothiazole with thiazolopyridine” to reduce the plasma protein binding and reduce drug clearance, which both equate to higher drug efficacy. Id. at 7. The Examiner finds that, alternatively, the skilled artisan would have been motivated “to replace the Cl with a -CF3 to arrive at the compound of claim 1 since similar potency would be expected based upon the data for 8e and 8j.” Id. Appellant argues the Examiner’s combination of prior art fails to render the claims obvious because “the Office has failed to provide adequate evidence that one skilled in the art would have selected Compound 8e as a lead compound.” Appeal Br. 9. Appellant submits that the Office has not sufficiently explained why the skilled artisan would have selected the identified compounds over “other more potent compounds identified in the table,” particularly when “it would have been clear to one skilled in the art that the data pointed to [Brown 139/Haydon 2] as the lead compound.” Id. Appeal 2020-004190 Application 16/053,537 7 Appellant also argues that, to the extent the Examiner has shown a prima facie case of obviousness, the compound of claim 1 “has an unexpected and improved in vivo half-life that renders it unobvious” over the Brown/Haydon compounds. Appeal Br. 5. Appellant also argues that the claimed compound is not obvious “because it is useful to prepare the compound recited in issued claim 11 of parent patent United States Patent Number 9,458,150.” Id. In support of the arguments, Appellant cites the Declaration of inventor Professor Edmond J. LaVoie under 37 C.F.R. § 1.132, dated April 30, 2019 (“LaVoie Dec.”). We discuss Appellant’s evidence further below. The issue on appeal is whether the preponderance of the evidence of record supports the Examiner’s conclusion of obviousness. 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.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Prima facie obviousness may be rebutted with evidence of secondary considerations and when such evidence is submitted, all of the evidence is considered anew. In re Piasecki, 745 F.2d 1468, 1472–73 (Fed. Cir. 1984). Secondary considerations include, inter alia, long-felt but unsolved needs, failure of others, and unexpected results. In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir. 1998). Appeal 2020-004190 Application 16/053,537 8 Analysis Looking to the Examiner’s findings and reasoning concerning the combination of Brown and Haydon, we agree that the compound of claim 1 would have been prima facie obvious. Each of compounds Brown 139/Haydon 2, Brown 218/Haydon 8j, and Brown 217/Haydon 8e were potent antibacterial compounds in multiple tests, making them suitable subjects for further drug development. Brown 162. Haydon confirmed that each of these compounds was effective in a murine model of staphylococcal infection, and further analyzed benefits in antibacterial effect conferred by specific chemical structures within the compounds. Haydon 3931–3. Haydon demonstrated the benefit of modifying Brown 218/Haydon 8j, which provides similar motivation to modify Brown 217/Haydon 8e based on its advantageous chemical structure. However, considering the totality of the evidence of record, we reach a different conclusion. The LaVoie Declaration was submitted in response to the Examiner’s statement in the non-final Office Action dated December 28, 2018, that the skilled artisan would have been “motivated to replace the Cl [of compound Brown 139/Haydon 2] with a -CF3 to arrive at the compound of claim 1 since similar potency would be expected.” LaVoie Dec. ¶ 3 (citing Office action at 8). Dr. LaVoie explains that the compound of claim 1, referred to in the Declaration as TXA-7-07, is a “synthetic intermediate that can be used to prepare the compound TXA-7-09.” LaVoie Dec. ¶ 5. Compound TXA-7-09 is reproduced below along with the corresponding 6-chloro Appeal 2020-004190 Application 16/053,537 9 compound TXY-5-41, which is identical except that the –CF3 of TXA-7-09 is replaced with a –C1. Id. ¶ 5. Dr. LaVoie declares that “[f]ollowing administration, TXA-7-09 and TXY-5-41 are hydrolyzed to the corresponding amides TXA-7-07 and PC190723,” shown below. Id. TXA-7-07 is the compound of claim 1. Dr. LaVoie declares that “the half-life of the hydrolysis product TXA- 7-07 was found to be 6.5 fold greater than the half-life of PC190723 after intravenous administration in mice when measured as described by Malvika Kaul, et al., Antimicrob. Agents Chemother., 2015, 59, 4845–4855” (“Kaul”). Id. Dr. LaVoie additionally declares that Kaul reported that “TXA-7-09 was found to be more potent than TXY-5-41 following intravenous administration in a murine septicemia model against Staphylococcus aureus infection (MSSA strain ATCC 19636).” Id. ¶ 6. Appeal 2020-004190 Application 16/053,537 10 Dr. LaVoie further declares that the bioavailability of the hydrolysis product TXA-7-07 (the compound of claim 1), is 95% compared to 29.6% of PC190723, the hydrolysis product of TXY-5-41. Id. ¶ 7. Finally, Dr. LaVoie declares that Kaul reported that “oral administration of 48 mg/kg of TXA-7-09 in the septicemia model described by [Kaul resulted in] a 100% cure from a methicillin-resistant S. aureus infection” while four times the dose of TXY-5-41 was required to obtain a similar response. Id. ¶ 8. “When TXY-5-41 was administered at 64 mg/kg there were 0% survivors.” Id. The Examiner responds that the “unexpected results argument is based on a comparison of non-prior art prodrug compounds” and that the comparison is not to a compound that is closer to the claimed compound. Ans. 7. We do not agree, as the declaration makes clear that metabolite PC190723 corresponds to compound Brown 139/Haydon 2, which is one of the compounds identified in the prior art and the compound upon which the claim was rejected. LaVoie Dec. ¶ 3 (citing Office action at 8). The Examiner further argues that “[t]here is no biological data for the compound of claim 1 in the specification or declaration.” Id. While the administered compounds compared are prodrugs, the record provides sufficient evidence to establish that the effects measured for each administered compound are caused by the metabolite, and that it is the metabolite that is biologically effective in each case. LaVoie Dec. ¶¶ 5–8. Moreover, TXA-7-07 provides unexpectedly superior results in that it has a significantly longer half-life, resulting from a lower clearance rate from the Appeal 2020-004190 Application 16/053,537 11 subject as well as a more effective antibacterial effect at lower doses than a similar compound. Id. Appellant’s data concerning the effectiveness of TXA-7-07 in vivo provides persuasive objective evidence of nonobviousness. The Examiner’s response relies heavily on the prima facie case, and the reasoning from Haydon suggesting that modification of compounds having benzothiazole by replacing the benzothiazole with thiazolopyridine would result in improved antibacterial function. Ans. 6−7. The Examiner has not, however, provided persuasive evidence or scientific reasoning explaining why the results Appellant has produced would have been expected. When the Examiner’s prima facie case is considered anew, in light of all the evidence of record, we are unpersuaded that claim 1 would have been obvious over Brown and Haydon. Appellant has provided persuasive argument and objective evidence of nonobviousness that outweighs the evidence of obviousness. Mintz v. Dietz & Watson, Inc., 679 F.3d 1372, 1379 (Fed. Cir. 2012) (“Obviousness requires . . . walk[ing] a tightrope blindfolded (to avoid hindsight)—an enterprise best pursued with the safety net of objective evidence.”) This is not a case where the prima facie case is so strong that it controls the obviousness determination. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007). We thus reverse the rejection of claim 1. Appeal 2020-004190 Application 16/053,537 12 CONCLUSION In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1 103 Brown, Haydon 1 REVERSED