Ex Parte FaulkDownload PDFPatent Trial and Appeal BoardOct 21, 201612270110 (P.T.A.B. Oct. 21, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 12/270,110 11113/2008 6449 7590 10/25/2016 ROTHWELL, FIGG, ERNST & MANBECK, P.C. 607 14th Street, N.W. SUITE 800 WASHINGTON, DC 20005 W. Page FAULK 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. 2932-151 1578 EXAMINER YAO, LEI ART UNIT PAPER NUMBER 1642 NOTIFICATION DATE DELIVERY MODE 10/25/2016 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): PTO-PAT-Email@rfem.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte W. PAGE FAULK 1 Appeal2015-0002644 Application 12/270,110 Technology Center 1600 Before JEFFREY N. FRED MAN, RICHARD J. SMITH, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a conjugate of a targeting protein with a bio-affecting molecule that is substantially free of dimers, trimers and aggregates, which have been rejected as anticipated. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE "The effectiveness of proteins conjugated with bio-affecting molecules has been demonstrated[.]" (Spec. 2.) "It has been determined[,] however, that the efficiency of such conjugates in treating stressed cells, 1 Appellant identifies the Real Party in Interest as Faulk Pharmaceuticals, Inc. (Br. 2.) Appeal2015-002644 Application 12/270, 110 such as cancer cells, is reduced by the presence of agglutinated conjugates or by the presence of conjugates of a bio-affecting molecule with protein fragments or with two or three protein molecules and is greatly enhanced when the protein to bio-affecting molecule ratio is closer to 1: 1." (Id.) Appellant's invention aims "to provide ... a homogeneous conjugate made by a more efficient method." (Spec. 3.) Claims 1-5, 8-10, and 13-142 are on appeal. Claim 1 is representative and reads as follows: 1. A substantially homogeneous material comprising a targeting protein conjugated with a bioaffecting molecule in a predetermined ratio of bio-affecting molecules to targeting protein molecules, wherein said targeting protein is attracted to receptors on target cells, wherein said substantially homogeneous material is prepared by a method comprising: a) adding a solution of said bioaffecting molecule to a solution of a glutaraldehyde linker material containing DMSO to a final concentration of a 1: 1 molar ratio ofbioaffecting molecule to glutaraldehyde resulting in the addition of one bioaffecting molecule to one glutaraldehyde molecule; and b) adding the bioaffecting molecule/glutaraldehyde combination to said targeting protein to produce a substantially homogeneous conjugate having a predetermined ratio of bioaffecting molecule to targeting protein; wherein said targeting protein-bioaffecting molecule conjugate is substantially free of dimers, trimers and aggregates. (Br. 25.) 2 Claims 6, 7, 11, and 12 are also pending, but stand withdrawn from consideration. (Br. 2.) 2 Appeal2015-002644 Application 12/270, 110 The following grounds of rejection by the Examiner are before us on review: 1. Claims 1-5, 8-10, and 13-14 under 35 U.S.C. § 102(b) as anticipated over Berczi, 3 as evidenced by Wang4 and Mesh word search Adriamycin. 2. Claims 1-5, 8-10, and 13-14 under 35 U.S.C. § 102(b) as anticipated over Page 5 as evidenced by Wang and Lai. 6 DISCUSSION A. Anticipation by Berczi The Examiner finds that Berczi teaches a "relatively homogeneous" conjugate mixture of Adriamycin (also known as Doxorubicin, as evidenced by the Mesh word search of Adriamycin) linked to transferrin, and that the conjugate has a molecular weight of 80 kDa. (Ans. 6; Final Action 3.) The Examiner explains that Wang demonstrates that Adriamycin is an apoptosis inducing agent. (Ans. 3; Final Action 3.) Regarding the homogeneous 3 Berczi et al., Adriamycin Conjugates of Human Transferrin Bind Transferrin Receptors and Kill K562 and HL60 Cells, 300(1) Archives of Biochem and Biophy, 356-63 (1993). 4 Wang et al., Doxorubicin Induces Apoptosis in Normal and Tumor Cells via Distinctly Different Mechanisms, 279 (24) J. Biological Chem., 25535- 43 (2004). 5 Page et al., U.S. Patent 5,208,323, issued May 1993. 6 Lai et al., Mechanism of action and spectrum of cell lines sensitive to a doxorubicin-transferrin conjugate, 41 (2) Cancer Chemother. Pharmacol., 155---60 (1998). The Examiner only referenced the abstract of Lai et al. (See Final Action 6.) 3 Appeal2015-002644 Application 12/270, 110 mixture, the Examiner notes that "Berczi states: the spectrophotometric analysis of peak 2 (fractions 21-27 in figure l[, a column chromatography analysis ofTRF-ADR conjugates, where fractions 21-27 exhibited a single peak,]) indicated that the average conjugation numbers of TRF-ADR conjugates were relatively homogenous (page 358, right col, line 3+)." (Final Action 3--4.) The Examiner finds that "the conjugate in each of lanes 2--4 and 7-8 of Figure 2 of Berczi[, reporting the results of analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of TRF-ADR conjugates eluted in fractions 21-27 of Figure 1,] is a single ban[d] at 80 kDa, free of dimers, trimers and aggregates." (Ans. 8; Final Action 4.) The Examiner notes that there "is no purity of 'substantially homogeneous"' defined in the Specification; rather, the Specification "defines the phrase 'substantially homogeneous' as that can be used without further purification." (Ans. 8.) The Examiner finds that the conjugate of Berczi "is used in the binding and cytotoxicity assays without further purification." (Ans. 8.) The Examiner concludes, in light of the foregoing, that the Berczi TRF-ADR conjugate meets the "structural and functional limitations of the conjugate recited" by the claims. (Ans. 8.) We agree with the Examiner's factual findings and conclusion that Berczi describes the product recited in claim 1. If the product in a product- by-process claim is the same as a product of the prior art, the claim is unpatentable even though the prior product was made by a different process unless "the prior art products do not necessarily or inherently possess the characteristics of [the] claimed product." In re Thorpe, 777 F.2d 695, 697- 98 (Fed. Cir. 1985). 4 Appeal2015-002644 Application 12/270, 110 Appellant's argument that "the recited method steps result in a conjugate with specific properties which are different from conjugates made using Berczi's method" (Br. 8) is not persuasive. Appellant contends that the SDS-PAGE results set forth in Berczi's Figure 2, and especially lanes 5 and 6 that show "the fractions containing the highest concentration of the monomer" and "considerable [dark] spots," demonstrate that Berczi' s process results in the formation of a "significant quantity" of dimers (Br. 8) and that, in addition to showing dimers in Figure 2, "Berczi mentions the presence of dimers" (Br. 9). We do not disagree with Appellant that Figure 2 demonstrates dimers in lanes 5 and 6, which correspond to eluted fraction 24 and 25 from the Sepharose column (Berczi 358 (Figs. 1 & 2); Br. 8-10 (discussing why "one skilled in the art would expect dimers to be present with the monomer in these fractions [containing the highest concentration of monomer, lanes 5 and 6 of the SDS-P AGE]]"), however, that fact does not address the material present in fractions 21-23, the results of the SDS-P AGE being set forth in Berczi's Figure 2, lanes 2--4. As the Examiner notes, each of lanes 2--4, shows a single band at 80 kDa and thus none demonstrates the presence of dimers. (Final Action 4; Ans. 8.) Appellant notes that the declaration of Dr. Klara Barabas, 7 one of the co-authors of Berczi, "discusses why the gels shown in Berczi cannot be used to confirm the absence of dimers, trimers and aggregates," including that "[ t ]he combination of a less sensitive stain [ Coomassie blue] and a lower protein concentration in lanes 2, 3 and 8 erroneously make it appear as 7 Original Declaration submitted Dec. 30, 2010. 5 Appeal2015-002644 Application 12/270, 110 if these fractions do not include dimers." (Br. 10-11.) However, that Coomassie blue is less sensitive than silver staining and that the concentration of protein in lanes 2 and 3 is less than in lanes 5 and 6 (Barabas Deel. i-fi-1 9--11) does not establish the presence of dimers in lanes 2 and 3. Furthermore, we note that lane 4 of Figure 2, appears to have a significant percentage of monomeric protein given the intensity of the stains at 80 kDa like lanes 5 and 6, yet Dr. Barabas does not even address the fact that lane 4, like lanes 2 and 3, and in contrast to lanes 5 and 6, also does not exhibit a band at 160 kDa. Dr. Barabas does not provide experimental evidence demonstrating dimers were present after chromatography, in lanes 2 and 3, or a silver stain of the TRF-ADR conjugate produced according to Berczi which might have demonstrated the presence of dimers in fractions 21 or 22, which correspond to the fractions analyzed in lanes 2 and 3. Thus, we accord little weight to Dr. Barabas' opinion, which is not grounded in any experimental proof or compelling scientific reasoning, that dimers were necessarily present in fractions 21 and 22 (lanes 2 and 3 of the SDS-P AGE gel), which opinion is in contrast to the experimental evidence provided in Berczi itself. See Velander v. Garner, 348 F.3d 1359, 1371 (Fed. Cir. 2003) ("In giving more weight to prior publications than to subsequent conclusory statements by experts, the Board acted well within [its] discretion."). Moreover, while Dr. Barabas asserts that after centrifugation, but before chromatography, smaller aggregates as well as dimers and trimers remained in solution (Barabas Deel. i1 5), even if it were true, that fact does not establish that any of eluted fractions 21-23 include dimers. Nor does the fact that Berczi indicates "a small percentage of dimeric forms was found" 6 Appeal2015-002644 Application 12/270, 110 (Berczi 358). (Barabas Deel. i-f 12.) Berczi's disclosure that only a "small percentage of dimeric forms was found" could reasonably be understood to mean the small percentage was found in the conjugated material eluted as a whole from the Sepharose CL-4B chromatography column, not each individual fraction collected. (Berczi 358.) That interpretation is consistent with lanes 2--4, which correspond to eluted fractions 21-23, only showing a single band at 80 kDa, representing monomeric TRF-ADR. (Berczi 358 (Fig. 2).) Even Dr. Barabas agrees that lanes 2 and 3, which are compositions arising after chromatography, have an "apparent absence of a stain indicative of transferrin: transferrin dimers" (Barabas Deel. i-f 9.) For the foregoing reasons, and contrary to the opinion of Dr. Barabas (Barabas Deel. i-f 12), we find insufficient evidence leading to a conclusion that the small percentage of dimeric forms noted by Berczi to have been "found" was found in each fraction eluted from the chromatography column. Moreover, even if we were to accept that some undetectable amount of dimer were present in fractions 21 and 22 (or even 23) (Barabas Deel. i-f 10), the claims require only that the conjugate be substantially free of dimer, trimer, or aggregates. There is no specific level of purity required by the claim or set forth by definition in the specification. We conclude that an "undetectable" amount that may be present in the eluted fractions 21, 22, and 23 is within the claim requirement of "substantially free." In light of the foregoing, we agree with the Examiner that Berczi discloses a product, specifically the product found in the tubes of eluted fractions 21, 22, and 23, that is a substantially homogeneous material comprising TRF-ADR conjugate monomer substantially free of dimers, 7 Appeal2015-002644 Application 12/270, 110 trimers, or other aggregates. The fact that dimers may be detectably found in other fractions does not negate the foregoing. Appellant's argument that the definition of "substantially homogeneous conjugate" provided in the Specification "excludes prior art conjugates which require gel filtration to remove the aggregates and thus the amount of dimers in figures 1 and 2 of Berczi would not meet the limitation of 'substantially free' or 'substantially homogenous' as recited in the present claims" (Br. 13-14) is also not persuasive. Initially, we note that claim 1 does not recite "substantially homogeneous conjugate," which is the phrase defined in paragraph 52 of the Specification to mean "that the conjugates can be used without further purification to remove protein dimers, polymers or aggregates." And, in any event, as just discussed, Berczi teaches obtaining fractions 21, 22, and 23, each of which are materials that are substantially homogeneous compositions of a TRF-ADR monomer substantially free of dimers. Appellant does not argue that, nor do we discern any reason why, the conjugates obtained in fractions 21, 22, and 23 could not "be used without further purification to remove protein dimers, polymers or aggregates." (Spec. i-f 52.) We find that, based on the disclosure in Berczi of the relative homogeneity of the conjugate produced, the Examiner has met his burden of establishing the microhomogeneity aspect of the claimed product is inherent to Berczi. Appellant asserts that Berczi' s process would result in a mixture of conjugates with different ratios of ADR to TRF because Berczi does not include DMSO in the glutaraldehyde solution when adding doxorubicin. (Br. 12.) However, simply asserting that Berczi does not employ the same 8 Appeal2015-002644 Application 12/270, 110 process as Appellant is not probative of whether Berczi's product does or does not have the claimed homogeneity of a predetermined ratio of TRF- ADR. Thus, we find that Appellant has not met its burden demonstrating that Berczi does not have the claimed microheterogeneity. See In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (holding that after a prima facie case is made out, the burden shifts to the applicant to prove a difference between the prior art compounds and the claimed compound). For the foregoing reasons, we agree with the Examiner that Berczi's conjugate in fractions 21, 22, and 23, would meet both structural and functional limitations of the conjugate recited in claim 1 and defined in the application. Claims 2-5, 8-10, and 13-14 have not been argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv). B. Anticipation by Page The Examiner finds that Page teaches a method of making a homogeneous conjugate comprising transferrin linked to doxorubicin, wherein the conjugate is denoted R-glutaraldehyde-M, where R is transferrin and Mis doxorubicin. (Final Action 4, 6; Ans. 9.) The Examiner further finds that Page teaches the conjugate made by this process "does not have a tendency to polymerize," which meets the limitation of "free of dimers, trimers, and aggregates." (Id.) The Examiner further finds that Page teaches a range for the ratio of R-M in the conjugate that can be as desired, including 5: 1 to 7: 1, as well as 1: 1. (Final Action 6.) The Examiner notes that Lai evidences that "transferrin binds and is attracted to the receptor expressed on [a] tumor cell." (Final Action 4; Ans. 6.) The Examiner further notes that 9 Appeal2015-002644 Application 12/270, 110 Page "teaches a method of using the conjugate in a cytotoxicity assay without further purification." (Ans. 10.) In view of the foregoing, the Examiner concludes that the Page TRF-ADR conjugate anticipates the claimed product-by-process. (Final Action 4, 1 O; Ans. 6.) We agree with the Examiner's factual findings regarding the conjugate of Page and conclusion that Page anticipates the claimed conjugate. Appellant argues that the process by which Page's doxorubicin- glutaraldehyde is produced is different from the process used to produce the claimed product, that Page "does not recognize the necessity of proper electrostatical balance" between DMSO and glutaraldehyde in forming the DOX-GLU complex, and that Page does not teach or suggest any methods for preventing the formation of dimers, trimers or aggregates. (Br. 15-1 7.) Appellant contends that "[ t ]he molar excess [of glutaraldehyde] used in Page results in the addition of more than one glutaraldehyde molecule to some molecules of doxorubicin which results in a mixture of conjugates with different ratios of DOX to TRF as well as dimers, trimers and aggregates." (Br. 18.) We do not find Appellant's arguments persuasive. While Appellant posits that polymerization occurs because a molar excess of glutaraldehyde to doxorubicin is used in Page and because "prior to the present invention, it was difficult to control the degree of conjugation" (Br. 21 (citing Faulk Declaration8)), Appellant provides no experimental evidence to support its assertion that Page's process results in "different 8 Declaration of Dr. W. Page Faulk submitted with response filed Oct. 30, 2013. 10 Appeal2015-002644 Application 12/270, 110 ratios of DOX to TRF as well as dimers, trimers and aggregates" (Br. 18). Page, on the other hand, teaches that the improved coupling method, which involves an intermediate glutaraldehyde activated doxorubicin derivative being coupled to TRF in DMSO, results in conjugates that "do not have a tendency to polymerize" (Page 3:65--4:23), as well as that are in a DOX:TRF ratio as desired (Page 6:25-30.) Page indicates that this lack of polymerization is the result of a method that produces conjugates that are "substantially pure." (Page 2: 63---65). The opinion testimony of an interested party, such as Dr. Faulk, is of little or no probative value in establishing that Page's teaching that the process produces a conjugate that does not have a tendency to polymerize, in fact, results in the production of dimers, trimers, and/or aggregates. Cf Perring B. V. v. Barr Laboratories, Inc., 437 F.3d 1181, 1188 (Fed. Cir. 2006) ("A witness's interest is always pertinent to his credibility and to the weight to be given to his testimony ... "). Moreover, Dr. Faulk's testimony does not address the particular procedure set forth in Page, but rather is a generic statement that "before the present invention, it was difficult to control the degree of conjugation." (Faulk Dec. i-f 4.) That assertion is not meaningful in demonstrating that Page's process results in dimers, trimers, and/or aggregates. Furthermore, it is well settled that mere lawyer's arguments and conclusory statements, which are unsupported by factual evidence, are entitled to little probative value. See, e.g., In re Geisler, 116 F .3d 1465, 1470 (Fed. Cir. 1997). The only "factual evidence" provided to support the argument in Appellant's brief that Page's conjugates polymerize despite 11 Appeal2015-002644 Application 12/270, 110 Page's contrary teaching, or that a mixture of conjugates with different ratios ofDOX to TRF is produced is the Declaration by Faulk, an interested party, and the bald unsupported statement in the brief, that the molar excess of glutraldehyde necessarily "results in the addition of more than one glutaraldehyde molecule to some molecules of doxorubicin which results in a mixture of conjugates with different ratios of DOX to TRF as well as dimers, timers and aggregates." (Br. 21.) We find Appellant's argument lacks sufficient factual basis to demonstrate the conjugate in Page is not substantially free of dimers, trimers, or aggregates or that the conjugate contains a predetermined ratio ofbio-affecting molecule to targeting protein. See In re Best, 562 F.2d at 1255. Claims 2-5, 8-10, and 13-14 have not been argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv). SUMMARY We affirm the rejection of claims 1-5, 8-10, and 13-14 under 35 U.S.C. § 102(b) as anticipated over Berczi, as evidenced by Wang and Mesh word search Adriamycin. We affirm the rejection of claims 1-5, 8-10, and 13-14 under 35 U.S.C. § 102(b) as anticipated over Page, as evidenced by Wang and Lai. 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). AFFIRMED 12 Copy with citationCopy as parenthetical citation