Ex Parte Masini et alDownload PDFPatent Trial and Appeal BoardSep 6, 201612555151 (P.T.A.B. Sep. 6, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 12/555, 151 09/08/2009 25006 7590 09/08/2016 DINSMORE & SHOHL LLP POBOX7021 TROY, MI 48007-7021 FIRST NAMED INVENTOR Michael A. Masini 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. MED-06203/29 1042 EXAMINER CHEN, SHIN LIN ART UNIT PAPER NUMBER 1632 NOTIFICATION DATE DELIVERY MODE 09/08/2016 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): docket@patlaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte MICHAEL A. MASINI and MAR TIN S. BANCROFT Appeal2014-007296 Application 12/555, 151 Technology Center 1600 Before FRANCISCO C. PRATS, JEFFREYN. FREDMAN, and TIMOTHY G. MAJORS, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal 1 under 35 U.S.C. § 134 involving claims to a method of synthesizing musculoskeletal tissue. The Examiner rejected the claims as failing to comply with the enablement requirement. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellants identify the Real Party in Interest as Medidea, LLC (see App. Br. 1 ). Appeal2014-007296 Application 12/555, 151 Statement of the Case Background "Musculoskeletal tissues are composed of a composite of cellular and matrix components[;] ... musculoskeletal tissues in living organisms have the ability to adapt to mechanical and physiologic changes throughout life" (Spec. ii 3). The Claims Claims 1, 2, 6, 9, 10, and 13-28 are on appeal. Independent claim 1 is representative and reads as follows: 1. A method of synthesizing musculoskeletal tissue, the method comprising the steps of: providing a cell culture vessel containing a cell culture medium; introducing at least one musculoskeletal precursor to the medium; applying a force to the musculoskeletal precursor in vitro through an actuator that mimics forces experienced by a bone in a body, whereby the precursor develops into a musculoskeletal tissue matrix having desired properties through the application of the force. The Issue The Examiner rejected claims 1, 2, 6, 9, 10, and 13-28 under 35 U.S.C. § 112, first paragraph, enablement (Ans. 2-8). The issue with respect to this rejection is: Does the evidence of record support the Examiner's conclusion that the Specification does not enable the claimed invention? 2 Appeal2014-007296 Application 12/555, 151 Findings of Fact Breadth of Claims 1. The Examiner finds that the "claims encompass synthesizing musculoskeletal tissue, such as bone tissue and bone-tendon-bone composite" (Ans. 3). 2. The Specification teaches that the musculoskeletal tissue encompasses "bone, cartilage, or ligament tissue produced by osteoblasts, chondroblasts, and fibroblasts, respectively. Pluripotential stem cells can differentiate into the various cell lines, depending upon the environment created by the culture medium and force construct utilized" (Spec. i-f 30). Presence of Working Examples 3. The Specification provides no working examples (see Spec. ,-r,-r 1-7 5). Amount of Direction or Guidance Presented 4. The Specification provides no specific details on the components for the cell culture medium to "induce growth of bone material on the scaffold" instead teaching generally that "culture medium components may include: protein sources, carbohydrates, fats, and minerals for deposition including calcium and phosphate. Any appropriate enzymes, co-enzymes, hormones or growth modifiers may be included as well" (Spec. ,-r 29). 5. The Specification teaches that "[a]ctuator 36 is preferably a stacked piezoelectric actuator, so as to provide stress (compression force) and/or strain (extensive force) to the scaffold and growing matrix through a displacement of the upper end of the scaffold. Other actuators may be used, 3 Appeal2014-007296 Application 12/555, 151 such as solenoids or electric motors" (Spec. i-f 30). The Specification teaches that the "force applied to the bone can also be scaled according to an estimate elastic modulus (Young's modulus, compression modulus, and similar) based on ultrasonic, x-ray, or other radiation absorption measurements" (Spec. i-f 45). State of the Prior Art and Unpredictability of the Art 6. Vacanti2 teaches that "tenocytes will adhere to synthetic biodegradable polymers[,] survive and multiply in vitro, and that tenocyte- polymer construct implantation in vivo results in formation of tendon with characteristics similar to normal mature tendon" (Vacanti 7:20-24). 7. Misawa3 teaches that "[a]rtificial bone is often utilized instead of autologous bones, but bone formation is not efficiently induced. Alternatives to the autogenous bone and artificial bone should be explored" (Misawa, Abstract). 8. Misawa teaches that the "major drawback of somatic stem cells is the limited proliferative capacity in vitro. On the other hand, embryonic stem cells can grow unlimitedly in vitro tissue culture and can differentiate into all types of the tissues cells. There is still difficulty in controlling such differentiation of embryonic stem cells" (Misawa, Abstract). 9. Spector4 teaches that "[f]or many connective tissues of the musculoskeletal system, with microstructures that reflect the mechanical environment, it may be more advantageous to regenerate the tissue in vivo 2 Vacanti et al., US 6,840,962 Bl, issued Jan. 11, 2005. 3 Misawa et al., Bone regeneration using embryonic stem cells, 12 ORGAN BIOLOGY 281 (2005). 4 Appeal2014-007296 Application 12/555, 151 than to fully engineer the tissue in vitro for subsequent implantation" (Spector 293, Abstract). 10. Spector teaches that "there is a growing consensus that the challenge of developing biomaterials for tissue engineering, regenerative medicine, and gene therapy exceeds the challenge that was faced in the cell biological work that led to the proliferation of cells in vitro" (Spector 293, Abstract). 11. Spector teaches that "it is important to point out that no 'tissue engineering' procedure, or any other treatment, has yet been successful in fully regenerating a tissue that does not have the capability to spontaneously regenerate ( eg bone)" (Spector 293, col. 2). 12. Salgado5 teaches that: in order to fully develop a tissue equivalent, there are five essential components: 1) in order to grow in a 3D manner similar to that found in vivo, cells will need a 3D support-a scaffold- that besides being a substrate for cell culture, will also confer mechanical stability to the construct until the neo-tissue is formed; 2) an adequate cell population to initiate the regenerative process; 3) growth and differentiation factors; 4) adequate cell culture methodologies and 5) accurate animal models that mimic the conditions that are pretended to regenerate in vivo. (Salgado 348). 4 Spector, M., Biomaterials-based tissue engineering and regenerative medicine solutions to musculoskeletal problems, 136 SWISS MED. WEEKLY 293-301 (2006). 5 Salgado et al., Adult Stem Cells in Bone and Cartilage Tissue Engineering, 1 CURRENT STEM CELL RESEARCH & THERAPY 345- 364 (2006). 5 Appeal2014-007296 Application 12/555, 151 13. Butler6 teaches that "[b ]iomechanical stimuli may in fact hold the key to producing regenerated tissues with high strength and endurance. However, many challenges remain, particularly for tissues that function within complex and demanding mechanical environments in vivo" (Butler, Abstract). 14. Butler teaches that: Although correlations between these forces and cell responses are abundant, elucidation of the mechanotransduction pathways is far from complete. The conversion of external forces to signaling pathways involves intracellular forces and associated molecular deformations (e.g., gap junctions on the cell membrane, the cytoskeleton, and DNA). The integration of these pathways with those associated with, for example, growth factor signaling is even less understood, but ultimately must be defined to provide a basis for bioreactor design. Since the application of mechanical stimuli invariably occurs in the context of biomolecular stimuli, biomechanicians will continue to contribute in these areas. (Butler 481, col. 1 ). 15. Butler teaches that: With current technologies, we are limited in our ability to engineer only tissues that possess modest structural and functional complexities. Thus, several challenges remain for TE/RM to widely succeed. These include challenges in mimicking the complex structure and function of the native ECM by controlling cell interactions with polymeric scaffolds so as to promote deposition of ECM that mimics native ECM, 6 Butler et al., The Impact of Biomechanics in Tissue Engineering and Regenerative Medicine, 15 TISSUE ENGINEERING: p ART B 477--484 (2009). 6 Appeal2014-007296 Application 12/555, 151 and in creating the complex architecture associated with native tissues and organs. (Butler 482, col. 2). 16. Freeman7 teaches that the "main aim of the current study was to test whether chondrocytes respond mechanically to compressive loading. The results demonstrate a very specific mechanical response, which has been used to determine the elastic and viscoelastic properties of the cell" (Freeman 318, col. 1 ). 17. Kampen8 teaches that: We conclude that under our experimental conditions, the in vivo effects of intermittent compressive force can be mimicked and studied in detail in vitro. Chondrocytes in our high-density tissue culture model respond to a mechanical stimulus of physiologic magnitude in a manner comparable with the in vivo response. The chondrocytes respond to intermittent compressive force by an increased synthesis of glycosaminoglycans in matrix proteoglycans. (Kampen 423, col. 2). Principles of Law When rejecting a claim under the enablement requirement of section 112, the PTO bears an initial burden of setting forth a reasonable explanation as to why it believes that the scope of protection provided by that claim is not adequately enabled by the description of the invention provided in the specification of the application. 7 Freeman et al., Chondrocyte Cells Respond Mechanically to Compressive Loads, 12 J. ORTHOPAEDIC RES. 311-320 (1994). 8 Kampen et al., Cartilage Response to Mechanical Force in High- Density Chondrocyte Cultures, 28 ARTHRITIS & RHEUMATISM 419--424 (1985). 7 Appeal2014-007296 Application 12/555, 151 In re Wright, 999 F.2d 1557, 1561---62 (Fed. Cir. 1993). "[T]he question of undue experimentation is a matter of degree. The fact that some experimentation is necessary does not preclude enablement; what is required is that the amount of experimentation 'must not be unduly extensive."' PPG Indus., Inc. v. Guardian Indus. Corp., 75 F.3d 1558, 1564 (Fed. Cir. 1996). Factors to be considered in determining whether a disclosure would require undue experimentation ... include ( 1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, ( 6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Analysis In addressing the Wands factors, the Examiner has provided substantial evidence that undue experimentation would have been required "to use any musculoskeletal precursor cells to synthesize musculoskeletal tissue, including bone and tendon, in vitro" (Ans. 4). The Examiner finds that "[i]t is unclear what kind of culture medium and what kind of musculoskeletal precursor cells would be used to generate bone and tendon in vitro" and that "[ e Jach type of cell medium, the type of scaffold, the type of precursor cells, and mechanical force used have to be considered individually in determining whether and what type of bone or bon-tendon-bone tissue can be formed in vitro" (Ans. 5). 8 Appeal2014-007296 Application 12/555, 151 Our analysis of the Wands factors yields the same result. The claims broadly encompass musculoskeletal tissue synthesis using a wide variety of cells including osteoblasts, chondroblasts, fibroblasts, and pluripotent stem cells into a wide variety of different musculoskeletal tissues including bone, cartilage, and tendon (FF 2). There are no working examples of a single musculoskeletal tissue synthesis using any cell to form any tissue (FF 3). The Specification does not provide detailed guidance regarding specific culture medium components for growing or differentiating cells (FF 4). Moreover, the Specification provides no specific details on the amount or directionality of forces necessary to obtain any specific types of tissue or using any particular types of cells, instead providing only general guidance regarding devices and forces (FF 5). The prior art cited by the Examiner evinces that induction of bone formation is difficult (FF 7), that stem cell differentiation is unpredictable (FF 8), and that musculoskeletal microstructures are preferably replicated in vivo rather than in vitro (FF 9). For example, Spector points out the high degree of unpredictability, stating that "that no 'tissue engineering' procedure, or any other treatment, has yet been successful in fully regenerating a tissue that does not have the capability to spontaneously regenerate ( eg bone)" (FF 11 ), while Salgado identifies five essential components in developing tissue equivalents (FF 12). Applying Salgado's essential components to the instant facts, Appellants' Specification does not address the specific growth and 9 Appeal2014-007296 Application 12/555, 151 differentiation factors or cell culture methodologies necessary to synthesize musculoskeletal tissue. Butler, published several years postfiling, states that "many challenges remain, particularly for tissues that function within complex and demanding mechanical environments in vivo" (FF 13) and established unpredictability by finding that even in 2009 "correlations between these forces and cell responses are abundant, elucidation of the mechanotransduction pathways is far from complete" (FF 14). The "failure of skilled scientists, who were supplied with the teachings that [Appellants] assert[] were sufficient and who were clearly motivated to produce [artificial musculoskeletal tissue], indicates that producing [artificial musculoskeletal tissue] was not then within the skill of the art." Genetech, Inc. v Novo NordiskA/S, 108 F.3d 1361, 1367 (Fed. Cir. 1997). Freeman and Kampen, cited by Appellants, do not disturb our analysis, because these references simply demonstrate that musculoskeletal cells such as chondrocytes respond to compressive loading (FF 16-17), but provide insufficient guidance on specific forces necessary to synthesize specific musculoskeletal tissues using particular starting cells. Therefore, even assuming a high level of skill in the art, consideration of the Wands factors supports the Examiner's conclusion that "one skilled in the art at the time of the invention would have to engage in undue experimentation to practice over the full scope of the invention claimed" (Ans. 7). See In re Fisher, 427 F.2d 833, 839 (CCPA 1970) ("[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art."). 10 Appeal2014-007296 Application 12/555, 151 Appellants contend that: According to Dr. Davisson, she "could make and/or use the invention based upon the claimed subject as described in the specification along with other information known by those skilled in the art, and she believes that steps of the process may be carried out to achieve the claimed results." (Davisson Affidavit, i-f3, emphasis added) Dr. Davisson disagrees with the Examiner that the specification fails to demonstrate how to synthesize musculoskeletal tissue by using a culture medium, at least one musculoskeletal precursor, such as osteoblast, chondroblast and fibroblast, etc., and applying force to the musculoskeletal precursor in vitro through an actuator. (App. Br. 2). Appellants contend that "the sole issue in this appeal is whether the Affidavit of Dr. Twana Davisson-clearly a person of skill in the art-should be deemed persuasive. For if Dr. Davisson's statements are persuasive, the pending claims of this application are enabling under 35 U.S.C §112, First Paragraph" (Reply Br. 1). We have considered the entire Davisson Declaration,9 and in particular the statements that "I also feel that those skilled in the art would know which culture medium formulation could be used to achieve the desired results, or could use published reports to ascertain that information" and that "I believe that the specification demonstrates how to synthesize musculoskeletal tissue through the use of a culture medium, at least one musculoskeletal precursor, such as osteoblast, chondroblast and fibroblast, etc., with force applied to the musculoskeletal precursor in vitro through an actuator" (Davisson Dec. i1i16-7). 9 Declaration of Dr. Twana Davisson, dated Feb. 4, 2012. 11 Appeal2014-007296 Application 12/555, 151 However, the Davisson Declaration does not identify any particular teachings in the Specification to support her conclusions regarding the synthesis of nmsculoskeletal tissue nor does the Davisson Declaration identify any prior art or contemporaneous published reports that are relied upon to support the enablement of the claimed invention. We do not find Appellants' argument persuasive that a statement in a Declaration alone, without supporting evidence, when weighed with the other Wands factors and the specific teachings of Spector, Salgado, and Butler demonstrating unpredictability (FF 9-15), is necessarily sufficient to overcome the enablement rejection. As the Examiner notes "[i]t is unclear what the 'other information known by those skilled in the art' mentioned by Dr. Davisson are and how those other information would enable the claimed invention" (Ans. 9). It is this evidentiary silence in the context of a factual scenario where a "search for the state of the art of synthesizing musculoskeletal tissue in vitro shows no evidence of synthesizing musculoskeletal tissue, including bone, tendon and bone-tendon-bone composite, in vitro" (id.) that undercuts the persuasiveness of the Davisson Declaration. In Wright, the court found unsupported affidavits insufficient to overcome an enablement rejection, finding that: [W]e note that each of these affidavits fails in its purpose because each merely contains unsupported conclusory statements as to the ultimate legal question .... Wright fails to point out with any particularity in this declaration, or in his arguments to this court, how the listed documents evidence that a skilled artisan in February of 1983 would have been able to carry out, without undue experimentation, the identification, 12 Appeal2014-007296 Application 12/555, 151 isolation, cloning, recombination, and efficacy testing steps required to practice the full scope of the appealed claims. In re Wright, 999 F.2d 1557, 1563 (Fed. Cir. 1993). See also In re Brandstadter, 484 F.2d 1395, 1406 (CCPA 1973) ("Affiants' statements that they would themselves be able to practice the invention are certainly some evidence on the ultimate legal question of enablement, but we must agree with the examiner's statement that 'the affidavits fail in their purpose since they recite conclusions and few facts to buttress said conclusions'".) Appellants also point to Freeman and Kampen to support selection of musculoskeletal precursor cells as well as the Specification (App. Br. 5; FF 2, 16, 17), but as already discussed above, these teachings lack specific details regarding the growth conditions, growth factors, specific matrices, specific loads, and other elements necessary to synthesize musculoskeletal tissue without undue experimentation. Even considering Freeman and Kampen, along with the Davisson Declaration, when balanced against the other evidence of record as discussed above, the preponderance of the evidence supports the Examiner's determination that claim 1 is not enabled. We think this situation is similar to In re '318, where the Court found that "[t]hus, at the end of the day, the specification, even read in the light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient." In re '318 Patent Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009). See also Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1325 (Fed. Cir. 2005) ("If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights 13 Appeal2014-007296 Application 12/555, 151 to 'inventions' consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the 'inventor' would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."). Conclusion of Law The evidence of record supports the Examiner's conclusion that the Specification does not enable the claimed invention. SUMMARY In summary, we affirm the rejection of claim 1 under 35 U.S.C. § 112, first paragraph, scope of enablement. Pursuant to 3 7 C.F .R. § 41.3 7 ( c )( 1 ), we also affirm the rejection of claims 2, 6, 9, 10, and 13-28, as these claims were not argued separately. 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 14 Copy with citationCopy as parenthetical citation