Ex Parte Mohapatra et alDownload PDFPatent Trial and Appeal BoardNov 19, 201813773749 (P.T.A.B. Nov. 19, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 13/773,749 02/22/2013 Subhra Mahapatra 136746 7590 11/21/2018 Thomas Horstemeyer (USF) 3200 Windy Hill Road, SE Suite 1600E Atlanta, GA 30339 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. 292103-1260 4516 EXAMINER KASSA, TIGABU ART UNIT PAPER NUMBER 1619 NOTIFICATION DATE DELIVERY MODE 11/21/2018 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): uspatents@thomashorstemeyer.com docketing@thomashorstemeyer.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte SUBHRA MOHAPATRA, SHY AMS. MOHAPATRA, MARK CHRISTIAN HOWELL, SURAJ KISHORE DIXIT, and CHUNY AN WANG Appeal2017-007736 Application 13/773,749 1 Technology Center 1600 Before RICHARD J. SMITH, RYAN H. FLAX, and DAVID COTTA, Administrative Patent Judges. COTT A, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to a micelle composition. The Examiner rejected the claims on appeal under 35 U.S.C. § 103(a) as obvious. We affirm. 1 According to Appellants, the real party in interest is the University of South Florida. App. Br. 3. Appeal2017-007736 Application 13/773, 7 49 STATEMENT OF THE CASE Claims 21-39 are on appeal. Claims 21 and 31 are illustrative and read as follows: 21. A composition comprising: a micelle, wherein the micelle is comprised of polyethylene glycolphosphatidylethanolamine (PEG-PE), dioleoylphosphatidyl-ehtanolamine (DOPE), and 3B-{N-(N' ,- N' -dimethlaminoethane )-carbamoyl] cholesterol (DC- cholesterol), wherein the micelle forms a hydrophobic core, wherein the micelle has a positive surface charge, wherein the PEG-PE is present at 1-10% w/w of the total micelle; and a Mn-oleate nanoparticle, where the Mn-oleate nanoparticle is encapsulated in the hydrophobic core, wherein the composition has relaxivities effective for functioning as a contrast agent. 31. A composition comprising: a micelle, wherein the micelle is comprised of polyethylene glycol-pysphatidyl ethanolamine (PEG-PE), dioleoylphosphatidyl-ehtanolamine (DOPE), and 3 B- {N-(N' ,-N' -dimethlaminoethane )-carbamoyl] chlolesterol (DC- cholesterol), wherein the micelle forms a hydrophobic core, wherein the micelle has a positive surface charge; and a Mn-oleate nanoparticle, where the Mn-oleate nanoparticle is encapsulated in the hydrophobic core, wherein the composition is formulated as an intranasal formulation and is capable of preferentially accumulating in the lungs. App. Br. 20, 21. 2 Appeal2017-007736 Application 13/773, 7 49 The Examiner rejected claims 21-39 under 35 U.S.C. § I03(a) as obvious over the combination of Liu, 2 Torchilin, 3 Sailor, 4 and Pan. 5 FINDINGS OF FACT 1. Liu discloses "complexes formed between biologically active substances and the emulsion and micellar formulations" that are "physically stable and their transfection activity is resistant to the presence of serum." Liu Abstract. These formulations are "useful in areas such as gene therapy or vaccine delivery." Id. 2. Torchilin discloses: "The present invention is directed to an improved drug delivery system comprising a targeted form of a polyethyleneglycol (PEG)/lipid-conjugated micelle, which is capable of stabilizing poorly soluble pharmaceutical agents and of increasing their delivery efficacy." Torchilin ,r 10. 3. Torchilin discloses that "[ t ]he micelles in the system of the invention have low critical micellar concentration and high kinetic stability, which provides great advantages in biodistribution, for example, accumulation at the site of a tumor." Id. Abstract. 4. Torchilin discloses: "Micelles prepared from conjugates of polyethyleneglycol (PEG) and diacyllipids, such as phosphatidylethanolamine (PE) are of particular interest." Id. ,r 28. 2 Liu et al., US Patent No. 6,120,794, issued Sept. 19, 2000 ("Liu"). 3 Torchilin et al., US Patent Publication No. 2006/0216342 Al, published Sept. 28, 2006 ("Torchilin"). 4 Sailor et al., US Patent Publication No. 2012/0059240 Al, published Mar. 8, 2012 ("Sailor"). 5 Pan et al., Sensitive and Efficient Detection of Thrombus with Fibrin- Specific Manganese Nanocolloids, CHEM. COMMUN., 3234--26 (2009) ("Pan"). 3 Appeal2017-007736 Application 13/773, 7 49 5. Sailor discloses: The disclosure provides compos1t10ns compnsmg a micelle hybrid nanostructure having bimodal imaging capacity and drug delivery capacity both in vivo and in vitro .... More particularly, the disclosure provides in specific embodiments, micellar hybrid nanostructure that comprise a magnetic nanostructure, at least one quantum dot, QD, and a therapeutic drug (e.g., an anti-cancer drug) within a single PEG-phospholipid micelle. Sailor ,r 5. 6. Sailor discloses: In particular embodiments, where the lipid species comprises a pegylated lipid, the total content of pegylated lipid, as a percentage of total lipid content, will be in the range of 1 % to approximately 20% or more. In other embodiments the range of pegylated lipid will be approximately 1-10%, approximately 1- 6%, approximately 1-5%, approximately 1--4% or approximately 1-3 %. In certain embodiments, the total content of pegylated lipid will be approximately 2.5%, approximately 4%, approximately 5%, approximately 10%, approximately 15% or approximately 20%. A complex may contain both pegylated and non-pegylated lipid of a particular type, for example, pegylated and non-pegylated DSPE. In certain embodiments, the total pegylated lipid content is no more than approximately 10%. Id. ,I 45. 7. Pan discloses: In this work, we report for the first time the synthesis and l\r1R characterization of "soft" type manganese oxide nanocolloid (]VhmOC) and manganese oleate nanocolloids (lvfanOL) incorporating divalent manganese. These nanocolloids are encapsulated by phospholipid and are constrained to the vasculature by size (> 120 nm) to avoid extravasation into non- target, non-clearance tissues within the mi.erial wall or beyond. lv1eta1s are uniquely entrapped within the core matrix to avoid unfavourable interactions with surface homing ligands or surrounding plasma proteins. These uniquely constructed nanoco11oids possess a long shelf-life stability and retain the 4 Appeal2017-007736 Application 13/773, 7 49 particle integrity for viable clinical translation. Pan 3234. 8. Pan discloses: In conclusion, we have successfully synthesized and demonstrated fibrin-specific "soft" type manganese nanocolloids with high relaxivity and detection sensitivity reaching to the low niv1 range. \,Vhile both agents possessed strong J\1R effectiveness, the incorporation of manganese as a metal complex allowed rnarkedly higher loading which provided greater T 1 w contrast than could be achieved with manganese oxide crystal encapsulation. J\1olecular imaging of intra vascular thrombus with these agents may allow early, direct identification of ruptured plaque, which could wan-ant aggressive medical or procedural intervention to preclude subsequent myocardial infarction or stroke. Id. at 3236. 9. The Specification discloses: It was recognized that phospholipid-encapsulated oleic acid coated nanoparticles are strongly protected from the outside aqueous environment by a tight hydrophobic layer and that this may prevent water protons from contacting the manganese nanoparticle surface and could therefore lead to a lowering of the relaxivity [H, Duan et al., The Journal of Physical Chemistry Letters 2008, 8127]. However, the DOPE component of the MLN s phospholipid micelle has two unsaturated fatty acid tails, which serve to increase the fluidity of the phospholipid micellar membrane. Since Tl contrast agents need to have direct interaction with the surrounding water protons to affect their relaxation times [Z. Zhen & J. Xie, Theranostics 2012, 2, 45], this increased fluidity could allow for more interaction of the manganese oxide nanoparticles and water protons. Spec. 23-24. 5 Appeal2017-007736 Application 13/773, 7 49 ANALYSIS Appellants argue claims 21-30 and 32-39 together. We designate claim 21 as representative. Liu discloses emulsion and micellar formulations that have the ability to form stable complexes with biologically active substances and that are useful for gene therapy and delivery of vaccines. FF 1. In finding claim 21 obvious, the Examiner found that Liu disclosed all of the elements of the claim, with the exceptions that Liu "does not specifically teach the incorporation of PEG-PE and the amount of PEG-PE as recited in claim 21" and that Liu "does not specifically teach the incorporation of hydrophobic manganese-oleate core." Final Act. 7, 9. With respect to the incorporation of PEG-PE, the Examiner found that Torchilin disclosed an improved micellar drug delivery system comprising polyethylene glycol and taught that "conjugates of polyethyleneglycol (PEG) and diacyllipids, such as phosphatidylethanolamine (PE) are of particular interest." Id. at 11. The Examiner also found that Sailor disclosed "micellar hybrid nano structure[ s] that comprise a magnetic nanostructure, at least one quantum dot, QD, and a therapeutic drug ( e.g., an anticancer drug) within a single PEG-phospholipid micelle." Id. at 11-12 (emphasis omitted). The Examiner further determined that Sailor disclosed micelle embodiments where the "pegylated lipid, as a percentage of total lipid content, will be in the range of 1 % to approximately 20% or more." Id. at 12 ( emphasis omitted). Based on the combined disclosures of Liu, Torchilin, and Sailor, the Examiner concluded that it would have been obvious to "modify the teachings of Liu et al. by incorporating PEG-PE in the micelle formulation 6 Appeal2017-007736 Application 13/773, 7 49 of Liu" because Torchilin teach that a micelle comprising PEG is "capable of stabilizing, inter alia, poorly soluble pharmaceutical agents and increasing their delivery efficacy." Id. at 10-11. Torchilin's micelles are also disclosed to have "low critical micellar concentration and high kinetic stability, which provides great advantages in biodistribution, for example, accumulation at the site of a tumor." Id. at 11. According to the Examiner, it would have been obvious to include PEG-PE in the amount claimed because Sailor provides "an indicative reference point in the preparation of micelles." Id. at 12. The Examiner also found that it would have been obvious to optimize PEG-PE content and that the skilled artisan would have had a reasonable expectation of success because "all the three references teach lipid based micelles." Id. at 13. With respect to incorporation of a hydrophobic manganese-oleate core, the Examiner found that Pan disclosed "the synthesis and MR characterization of 'soft' type manganese oxide nanocolloid (ManOC) and manganese oleate nanocolloids (ManOL) incorporating divalent manganese." Id (emphasis omitted). The Examiner concluded that it would have been obvious to incorporate a manganese-oleate core in Liu's micelle because Pan teaches "manganese-oleate will add a significant capability for imaging in diagnosis and treatment." Id. at 13. With respect to the limitation requiring that the composition have "relaxivities effective for functioning as a contrast agent," the Examiner found that, "since the composition taught by the references set forth above contain[ s] substantially identical or similar ingredients as the instantly claimed composition[,] the composition taught by the reference[ s] above 7 Appeal2017-007736 Application 13/773, 7 49 would necessarily ha[ ve] relaxivities effective for functioning as a contrast agent." Id. We agree with the Examiner that the composition of claim 21 would have been obvious over the cited references. We address Appellants' arguments below. Appellants argue that the Examiner improperly relies on hindsight bias, using "the inventor's disclosure as a blueprint for piecing together the prior art." App. Br. 12. We are not persuaded. As our reviewing court's predecessor stated inJn re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971): Any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from applicant's disclosure, such a reconstruction is proper. Here, we find no evidence that the Examiner gleaned anything from Appellants' disclosure in reaching the conclusion that claim 21 would have been obvious. It is clear from the Examiner's discussion of the references that the Examiner relied only on what was known to one skilled in the art. Appellants argue that the "only way [for] one of ordinary skill in the art to arrive at the claimed composition would be to test each of the millions or more of possible combinations resultant from the combination of Liu, Torchilin, Sailor, and Pan because the art fails to establish any particular guidance on the particular selection of micelle component(s)." App. Br. 16. We are not persuaded. The suggestion to incorporate PEG-PE in Liu's micelle flows from specific disclosures in the cited prior art. Liu teaches micellar formulations that are useful for gene therapy and vaccine delivery. FFl. Torchilin 8 Appeal2017-007736 Application 13/773, 7 49 discloses that a micellar formulation incorporating PEG "is capable of stabilizing poorly soluble pharmaceutical agents and of increasing their delivery efficacy" and provides "great advantages in biodistribution." FF2, FF3. Torchilin further discloses that micelles prepared with PEG-PE "are of particular interest." FF4. Accordingly, we agree with the Examiner that it would have been obvious to incorporate PEG-PE in Liu's micellar formulations in order to take advantage of the stability, delivery efficiency, and biodistribution advantages provided by PEG-PE. Final Act. 10-13. It would also have been obvious to include PEG-PE in the amount claimed based on Sailor's disclosure of hybrid micelles having imaging and drug delivery capacity that incorporate PEG in the range of 1-20%. FF5, FF6. We agree with the Examiner that Sailor's disclosure provides "an indicative reference point in the preparation of micelles" and that it would have been "obvious to optimize the amounts of ingredients." Final Act. 12, 13. The suggestion to use a hydrophobic manganese-oleate core also flows from specific teachings in the art. Pan discloses that manganese oleate nanocolloids "avoid unfavourable interactions ,vith surface homing ligands or surrounding plasma proteins," have '"a long shelf-life stability," "retain the particle integrity for viable clinical translation," "possessed strong l\l[R effectiveness," and "may allow early, direct identification of ruptured plaque." FF7, FF8. Incorporating a manganese-o1eate core in Liu's micelle does not require selecting one possible component from arnong millions, but rather flmvs from Pan's specific teachings of the advantages of manganese oleate nanocolloids. Accordingly, we agree with the Examiner that it would have been obvious to incorporate a manganese-oleate core in Liu's micelle 9 Appeal2017-007736 Application 13/773, 7 49 to "add a significant capability for imaging in diagnosis and treatment." Final Act. 13. Appellants argue that the art is unpredictable, as reflected in Liu's testing of multiple formulations to assess functionality and Torchilin's teaching that the compatibility between a loaded drug and a specific micelle is unpredictable. App. Br. 14. We are not persuaded because, as discussed above, the combination of elements recited in the claims are specifically suggested in the art. Moreover, Torchilin teaches that micelles incorporating PEG stabilize poorly soluble drugs and, as the Examiner points out, Liu "demonstrate[d that] different lipids at various concentration ranges were able to provide stable micelles that are useful for the delivery of actives." FF2; Ans. 3--4. Appellants argue that the Examiner "disregards" the limitation of claim 21 requiring that "the composition has relaxivities effective for functioning as a contrast agent." Reply. Br. 9. Appellant contends that coatings such as oleate can affect relaxivities. We are not persuaded. [I]t is elementary that the mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not cause a claim drawn to those things to distinguish over the prior art. Additionally, where the Patent Office has reason to believe that a functional limitation asserted to be critical for establishing novelty in the claimed subject matter may, in fact, be an inherent characteristic of the prior art, it possesses the authority to require the applicant to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on. In re Best, 562 F.2d 1252, 1254--55, (CCPA 1977) (quoting In re Swinehart, 439 F.2d 210, 212-13 (CCPA 1971)). The Examiner did not disregard this limitation, but rather found it to be inherently present because the 10 Appeal2017-007736 Application 13/773, 7 49 composition rendered obvious by the cited art would have the same components as the claimed composition and would thus necessarily have "relaxivities effective for functioning as a contrast agent." Final Act. 13. Following the findings of the Examiner, Appellants have not shown them to be incorrect or that the obvious prior art compositions would not have the claimed property. Appellants argue that the Specification "teaches that the effectiveness of Mn as a contrast reagent is greatly influenced by coatings, such as oleate." App. Br. 15. Appellants further argue: One of skill in the art, while hoping that they would be successful, would appreciate that further encapsulating the Mn- oleate nanoparticles in a micelle made of at least 3 different components with no established role or effect on contrast properties would not reasonably be expected to form micelles that function as contrast agents as it would be 1) unknown and unpredictable if Mn-oleate particles would escape encapsulation by the micelle and, even if so, to what degree and 2) unknown and unpredictable what effect the additional lipid layer of the micelle would have on the ability of the Mn-oleate nanoparticles to interact with water protons to attain appropriate relaxivities to function as a contrast agent should the Mn-oleate particles not escape encapsulation by the specific micelle formulation claimed. Id. 15. We are not persuaded. Pan discloses that manganese oleate nanocolloids have "high relaxivity." FF8. Appellants do not identify persuasive evidence to support their assertion that it was not known whether these nanocolloids would "escape encapsulation by the micelle." See, Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989) ("Attorneys' argument is no substitute for evidence."); In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). Appellants 11 Appeal2017-007736 Application 13/773, 7 49 cite the Specification, but the passage cited as support for Appellants' position does not suggest a potential for the contrast agent to escape encapsulation. See FF9. The Specification does suggest that preventing the manganese nanoparticles from contacting water protons may lower relaxivity (id.), but Appellants do not identify persuasive evidence suggesting that the skilled artisan would expected the micelle suggested by Liu, Torchilin, and Sailor to prevent water protons from contacting an encapsulated contrast agent. In this regard, we note that Sailor discloses a micelle "having bimodal imaging capacity and drug delivery capacity." FF5. Appellants argue that the amounts of PEG disclosed in Sailor cannot be applied to the incorporation of PEG-PE as disclosed in Torchilin. App. Br. 15. We are not persuaded because, as Appellants concede, Sailor discloses ranges for incorporation of "a general PEG-phospholipid." Id. 15. We find that the skilled artisan would reasonably understand these general ranges to also be applicable to the specific PEG-phospholipid disclosed by Torchilin- i.e. PEG-PE. Appellants do not identify persuasive evidence to the contrary. Accordingly, we affirm the Examiner's rejection of claim 21. Because they were not argued separately, claims 22-30 and 32-39 fall with claim 21. Appellants argue that claim 31 is patentable for the same reasons as claim 21. We are not persuaded for the reasons discussed above. In addition, Appellants argue that claim 31 is patentable because it recites that "the composition is formulated as an intranasal formulation and is capable of preferentially accumulating in the lungs." Appellants argue that 'just 12 Appeal2017-007736 Application 13/773, 7 49 because something can be administered nasally does not necessarily or predictably mean that it would accumulate in the lungs." App. Br. 17. We are not persuaded because, as the Examiner explained, "the combination of the references teach a substantially structurally identical or similar micelle composition." Ans. 13. In re Best, 562 F.2d at 1255. Accordingly, we also affirm the Examiner's rejection of claim 31. SUMMARY For the reasons set forth herein and the reasons set forth in the Examiner's Answer and Final Office Action, we affirm the Examiner's rejection of claims 21-39 under 35 U.S.C. § 103(a) as obvious over the combination of Liu, Torchilin, Sailor, and Pan. 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)(l )(iv). AFFIRMED 13 Copy with citationCopy as parenthetical citation