Ex Parte Kraus et al

Patent Trial and Appeal BoardJun 15, 2018

13508986 (P.T.A.B. Jun. 15, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 13/508,986 08/22/2012 99562 7590 06/19/2018 Vedder Price P.C. 1633 Broadway, 31st Floor New York, NY 10019 FIRST NAMED INVENTOR Gottfried Kraus 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. 45980.00.2012 2950 EXAMINER KARPINSKI, LUKE E ART UNIT PAPER NUMBER 1616 NOTIFICATION DATE DELIVERY MODE 06/19/2018 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): ipdocketny@vedderprice.com ksoto@vedderprice.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte GOTTFRIED KRAUS and ROBERT ESKES 1 Appeal2017-000009 Application 13/508,986 Technology Center 1600 Before RICHARD M. LEBOVITZ, RY ANH. FLAX, and DEVON ZASTROW NEWMAN, Administrative Patent Judges. FLAX, Administrative Patent Judge. DECISION ON APPEAL This is a decision under 35 U.S.C. Â§ 134(a) involving appealed claims directed to a method for a large-scale manufacture of a squalene-containing oil-in-water emulsion. The Examiner's rejection of claims 1, 5, 10, 11, 14, and 25-30 under 35 U.S.C. Â§ 103(a) is appealed. We have jurisdiction under 35 U.S.C. Â§ 6(b). We reverse. 1 The Real Party in Interest is identified as "Novartis AG." Appeal Br. 1. Appeal2017-000009 Application 13/508,986 STATEMENT OF THE CASE The Specification states: The vaccine adjuvant known as 'MF59' [1-3] is a submicron oil- in-water emulsion of squalene, polysorbate 80 (also known as Tween 80), and sorbitan trioleate ( also known as Span 85). It may also include citrate ions e.g. 1 OmM sodium citrate buffer. The composition of the emulsion by volume can be about 5% squalene, about 0.5% Tween 80 and about 0.5% Span 85 .... . . . MF59 is manufactured on a commercial scale by dispersing Span 85 in the squalene phase and Tween 80 in the aqueous phase, followed by high-speed mixing to form a coarse emulsion. This coarse emulsion is then passed repeatedly through a microfluidizer to produce an emulsion having a uniform oil droplet size. . .. [T]he microfluidized emulsion is then filtered through a 0.22 Âµm membrane in order to remove any large oil droplets, and the mean droplet size of the resulting emulsion remains unchanged for at least 3 years at 4 Â°C. Spec. 1:8-19. Independent claim 1, reproduced below, is representative: 1. A method for a large-scale manufacture of a squalene- containing oil-in-water emulsion, comprising steps of: (i) providing a first emulsion having a first average oil droplet size, wherein the first average oil droplet size is 5000 nm or less and/or wherein the number of oil droplets having a size of > 1.2 Âµm in the first emulsion is 5 x 1011 /ml or less; (ii) microfluidizing the first emulsion to form a second emulsion having a second average oil droplet size which is less than the first average oil droplet size, wherein the number of oil droplets having a size of > 1.2 Âµm in the second emulsion is 5 x 1010 /ml or less; and (iii) filtrating the second emulsion using a first hydrophilic polyethersulfone membrane layer having a pore size > 0.3 Âµm and a second hydrophilic polyethersulfone membrane layer 2 Appeal2017-000009 Application 13/508,986 having a pore size < 0.3 Âµm, thereby providing a squalene- containing oil-in-water emulsion, wherein at least one of the first and the second hydrophilic polyethersulfone membrane layers is an asymmetric membrane, wherein the squalene-containing oil-in-water emulsion has a volume of more than or equal to 50 liters; and, (iv) filling the oil-in-water emulsion into one or more sterile closed systems. Appeal Br. 23 (Claims App'x). The following rejection is appealed: Claims 1, 5, 10, 11, 14, and 25-30 stand rejected under 35 U.S.C. Â§ I03(a) over Ott,2 Schloss, 3 and Konan. 4 Final Action 3. DISCUSSION "[T]he examiner bears the initial burden, on review of the prior art or on any other ground, of presenting aprimafacie case ofunpatentability. If that burden is met, the burden of coming forward with evidence or argument shifts to the applicant." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). "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'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007). However, "[r]ejections on obviousness grounds cannot be sustained by mere conclusory statements; 2 Gary Ott et al., The Adjuvant MF59: A 10-Year Perspective in Chapter 12 Methods, in 42 MOLECULAR MEDICINE: VACCINE ADmVANTS: PREPARATION METHODS AND RESEARCH PROTOCOLS 211-28 (D.T. O'Hagan ed. 2000) ("Ott"). 3 WO 2009/155401 Al (pub. Dec. 23, 2009) ("Schloss"). 4 Yvette N. Konan et al., Preparation and Characterization of Sterile and Freeze-Dried Sub-200 nm Nanoparticles, 233 INT'L J. PHARMACEUTICS 239- 52 (2002) ("Konan"). 3 Appeal2017-000009 Application 13/508,986 instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness." Id. at 418 (quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006)). The Examiner determined the appealed claims would have been obvious over the combination of Ott, Schloss, and Konan. Final Action 3- 13; Answer 2-7. We address Appellants' arguments below. Rejected claim 1 recites that "at least one of the first and the second hydrophilic polyethersulfone membrane layers is an asymmetric membrane." Appellants argue the cited prior art does not teach or suggest use of an asymmetric membrane. Appeal Br. 6, 8-9, 18. Appellants contend "a double layer filter and an asymmetric filter are different things." Id. at 18. Appellants also argue that PES (polyethersulfone) filters can be either hydrophilic or hydrophobic and the prior art (Schloss) does not specify a type. Id. at 12. The Examiner contends that the idea of an asymmetric membrane is rendered obvious by Ott and Konan. Both references teach filtration with more than one filter having a different pore size to avoid clogging. An asymmetric filter is nothing more than a single filter element with one pore size at one end and a different pore size at the other end, said filter would achieve the same effect as two different filter membranes with different pore sizes used in-line. Answer 2. The Examiner also states that "Konan exemplifies a hydrophilic PES filter (EXPRESS) which has a PES pre-filter." Id. at 6. As an initial matter, we note that the claim term "asymmetric membrane" is expressly defined by Appellants' Specification as: one in which the pore size varies from one side of the membrane to the other e.g. in which the pore size is larger at the entrance 4 Appeal2017-000009 Application 13/508,986 face than at the exit face. One side of the asymmetric membrane may be referred to as the "coarse pored surface", while the other side of the asymmetric membrane may be referred to as the "fine pored surface". Spec. 14:23-27. Thus, this is the interpretation we apply to the term "asymmetric membrane." The Examiner's points on the teachings of Konan are not entirely clear, but the Examiner inferentially contends that the Express filter disclosed by Konan renders obvious the asymmetry and hydrophilicity limitations of the claimed filter(s). Final Action 5; Answer 3. The Examiner provided no evidence on this determination beyond the conclusion. Appellants did not provide evidence to the contrary, but, in the absence of evidence supporting the Examiner's conclusion, it was not Appellants' burden to do so: "the examiner must provide some evidence or scientific reasoning to establish the reasonableness of the examiner's belief that the functional limitation is an inherent characteristic of the prior art" before the burden is shifted to Applicants to disprove the inherency. Ex parte Skinner, 2 USPQ2d 1788, 1789 (BP AI 1986). There is no evidence on appeal that the Express filter is hydrophilic or asymmetric. The Examiner's determination is merely conclusory on this issue. On the issue of the claimed asymmetry, the Examiner also determined that the prior art suggested such asymmetry because it disclosed two separate filters having respectively different pore sizes, used together, and thus providing an asymmetric combination of membranes. Answer 2-3. In light of the construction of "asymmetric membrane" based on its definition in the Specification, as discussed above, we do not consider the prior art's disclosure of two separate filters having different sized pores to meet the 5 Appeal2017-000009 Application 13/508,986 claimed filter. The Examiner has not provided persuasive reasoning or evidence as to why such prior art filters would have rendered obvious the claim element of a single asymmetric filter ( claimed as being used with a second filter). Appellants further argue Konan is not combinable with Ott and Schloss absent improper use of hindsight because Konan does not filter emulsions, but filters polyester nanoparticle suspensions. Appeal. Br. 9. The Examiner responds that Ott and Schloss are both drawn to sterilization filtration of squalene containing emulsions, Schloss further teaches PES filters and sizes thereof, Konan is drawn to sterilization filtration using PES filters and is used to teach specific types of PES filters as well as known filtration steps including pre-filtration with a PES filter ( examples, Express hydrophilic PES 0.2 micron filter with a 0.5 micron PES prefilter). Answer 3. The Examiner further responds that Ott teaches filtration of, filter sizes for, and particles sizes for squalene containing emulsions; Schloss teaches filtration of squalene emulsions with PES type filters along with filter sizes and particle sizes; and Konan teaches sterilization filtration using a PES pre-filter along with a PES filter and that pre-filtration reduces clogging. Given these teachings it would have been obvious to filter a squalene containing emulsion with a PES pre- filter with a pore size of 50 microns, and a PES filter having a pore size of20 microns (Konan EXPRESS examples). As the art teaches pre-filtration is effective at reducing clogging, it would have been obvious to use an asymmetric filter to further reduce large particles from clogging the 20 micron filter and reduce the need to change filters. Id. at 3--4. On this issue, the Examiner's rationale is reasonable and we discern no error therein. A prior art reference is analogous and thus can be used in 6 Appeal2017-000009 Application 13/508,986 an obviousness combination if it "is from the same field of endeavor, regardless of the problem addressed" or "is reasonably pertinent to the particular problem with which the inventor is involved," even if it is not within the inventor's field of endeavor. Unwired Planet, LLC v. Google Inc., 841 F.3d 995, 1000--01 (Fed. Cir. 2016) (quoting In re Clay, 966 F.2d 656, 658-59 (Fed. Cir. 1992)). It would be logical for the skilled artisan to consult and combine the Schloss reference in view of the Ott reference on the issue of filter materials and particle and pore sizes for producing squalene containing emulsions. It would also be logical for the skilled artisan to consult and combine Konan in view of Schloss regarding filtering techniques (e.g., dual PES filters) as both references teach similar filter materials and Konan teaches a good reason to do so, i.e., to reduce clogging when filtering. Appellants also provide data (table reproduced below) comparing the use of PES and dual-filtering using asymmetric filters as claimed versus using other, symmetric filter materials, in one example including using only one filter, as evidence that only the claimed combination provides effective recovery. Id. at 10. 7 Appeal2017-000009 Application 13/508,986 Regarding the data identified by Appellants, above, Appellants argue that they represent unexpectedly superior results so as to overcome a prima facie case for obviousness over the cited prior art. Appeal Br. 20-21. The Examiner responds that the data presented by Appellants' Specification (Tables 1--4) "does not show a true side by side comparison. More than one parameter is altered wherein a PVDF filter is used and a symmetric type vs. asymmetric type filter is used. Further, one would have expected that the use of a different filter would result in a different product recovery." Answer 4. On this issue we conclude the Examiner has the better position. "To be particularly probative, evidence of unexpected results must establish that there is a difference between the results obtained and those of the closest prior art, and that the difference would not have been expected by one of ordinary skill in the art at the time of the invention." Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014). Here, as indicated by the Examiner, it is not clear precisely why better recoveries were made as there are several variables at play. Also, the data presented is not compared to the closest prior art and it is unclear what results would have been expected or that Appellants' results were unexpected. For the reasons above, particularly because there is no evidence that the prior art taught or suggested the asymmetric and hydrophilic filter/membrane claim elements, we conclude the Examiner has not set forth a prima facie case for obviousness and reverse the outstanding rejection. 8 Appeal2017-000009 Application 13/508,986 SUMMARY The obviousness rejection is reversed. REVERSED 9