Wayne State University et al.

Patent Trials and Appeals Board

Mar 30, 2022

2020004873 (P.T.A.B. Mar. 30, 2022)

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. 15/277,877 09/27/2016 Kannan Rangaramanujam ATL/WSU 10-978 CON 4904 144710 7590 03/30/2022 National Institutes of Health c/o Pabst Patent Group LLP 1355 Peachtree Street Suite 800 Atlanta, GA 30309 EXAMINER WESTERBERG, NISSA M ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 03/30/2022 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@pabstpatent.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte KANNAN RANGARAMANUJAM, SUJATHA KANNAN, ROBERTO ROMERO, RAGHAVENDRA NAVATH, and ANUPA MENJOGE Appeal 2020-004873 Application 15/277,877 Technology Center 1600 BEFORE ULRIKE W. JENKS, TAWEN CHANG, and JOHN E. SCHNEIDER, Administrative Patent Judges. SCHNEIDER, Administrative Patent Judge. Appeal 2020-004873 Application 15/277,877 2 DECISION ON APPEAL STATEMENT OF THE CASE Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 36, 37, 39-48, 50, 51, 57, and 58.2 We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. CLAIMED SUBJECT MATTER The claims are directed to biocompatible nanosized hydrogel particles suitable for injectable delivery of therapeutic agents for treatment of diseases or disease states and also for bioimaging purposes. Claim 36, reproduced below, is illustrative of the claimed subject matter: 36. A composition comprising a poly(amidoamine) (PAMAM) dendrimer covalently conjugated via terminal functional groups to amino acid linkers, wherein the terminal functional groups of the dendrimer are selected from the group consisting of amine, carboxylic acid, and hydroxyl groups, wherein at least 59% of the total terminal functional groups of the PAMAM dendrimer are conjugated to an amino acid linker. wherein the amino acid linkers after conjugation to the dendrimer are covalently bound to one of two different chemically reactive groups two produce PAMAM dendrimers having covalently bound thereto via the amino acid linkers at least two different chemically reactive groups. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies the real parties in interest as Wayne State University and the United States of America as represented by the Secretary, Department of Health and Human Services. Appeal Br. 2. 2 Claims 49 and 52-56 are pending in the application but have been withdrawn from consideration. Final Act. 1. Appeal 2020-004873 Application 15/277,877 3 REFERENCES The prior art relied upon by the Examiner is: Name Reference Date Li et al. (Li ‘968) US 2003/0232968 A1 Dec. 18, 2003 Epstein et al. US 2005/0214286 A1 Sept. 29, 2005 Yang et al. WO 2010/017184 A2 Feb. 11, 2010 Weiner et al., Dendrimer-Based Metal Chelates: A New Class of Magnetic Resonance Imaging Contrast Agents, 31Mang. Reson. Med 1 (1994) Li et al., Poly(vinyl alcohol) nanoparticles prepared by freezing-thawing process for protein/peptide drug delivery, 56 J. Controlled Release 117 (1998) (Li 1998) Lambat et al., An Investigation into the Neuroprotective Properties of Ibuprofen, 15 Metabolic Brain Disease 249 (2000) Majoros et al., PAMAM Dendrimer-Based Multifunctional Conjugate for Cancer Therapy: Synthesis, Characterization, and Functionality, 7 Biomacromolecules 572 (2006) Navath et al., Dendrimer-drug conjugates for tailored intracellular drug release based on glutathione levels, 19 Bioconjug. Chem. 2246 (2008) (Navath 2008) Mishra et al., Surface-Engineered Dendrimers: a Solution for Toxicity Issues, 20 J. Biomaterials Sci. 141 (2009) Wang et al., The decrease of PAMA dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress, 20 nanotechnology 1 (2009) Navath et al., Stimuli-responsive star poly(ethylene glycol) drug conjugates for improved intracellular delivery of the drug in neuroinflammation, 142 J. Controlled Release 447 (2010) (Navath 2010) REJECTIONS The claims have been rejected as follows: Claims 36, 37, 39-48, 50, 51, and 58 have been rejected under 35 U.S.C. § 112(a) for failure to comply with the written description requirement. Appeal 2020-004873 Application 15/277,877 4 Claims 36, 37, 39-42, 45, 50, and 58 have been rejected under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968 and Wiener. Claim 43 has been rejected under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968, Wiener, and Wang. Claim 46 has been rejected under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968, Wiener, and Epstein. Claim 47 has been rejected under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968, Wiener, and Majoros. Claims 48 and 57 have been rejected under 35 U.S.C. 0167 103 as unpatentable over Mishra in view of Li ‘968, Wiener, and Navath 2008. Claims 41-44 have been rejected under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968, Wiener, Navath 2008, Navath 2010, and Yang. Claim 51 has been rejected under 35 U.S.C. § 103 as unpatentable over over Mishra in view of Li ‘968, Wiener, Navath 2008, Navath 2010, Yang, and Li 1998. OPINION Written Description The issue with respect to this rejection is whether the Examiner has properly determined that the disclosure of the application relied upon fails to reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date. The Examiner finds the current claims are not supported by the present Specification. Ans. 3. The Examiner finds that, while the Specification supports the claimed ranges of conversion, the Specification Appeal 2020-004873 Application 15/277,877 5 lacks support for claims that do not recite a size limitation for the dendrimers. Id. Appellant contends that the surface chemistry discussed in the Specification is applicable to all generations of PAMAM dendrimers regardless of the dendrimer size. Appeal Br. 9-10; Reply Br. 4-5. Appellant points to the present Specification where it teaches the specific conditions required to produce the recited yields, which are applicable regardless of the dendrimer size or generation. Appeal Br. 10; Reply Br. 5. Appellant also contends that the Examiner has failed to put forth any evidence to support the contention that one skilled in the art would not recognize in Applicants’ disclosure a description of the claimed subject matter. Appeal Br. 11. We have considered the positions of the Examiner and Appellant and find Appellant has the better position. As Appellant points out, the Specification teaches the conditions for modifying the dendrimers that are applicable to a wide range of dendrimers, not simply those recited in the Specification. For example, the Specification teaches High yields were achieved in the coupling reactions since an excess of amino acid could be used, and the unreacted material could later be removed by a simple dialysis process. Conversions 70-90% of hetero-bifunctional dendrimers were obtained by carrying out the reactions in mild simplistic conditions such as water/dimethylsulfoxide/dimethyl formamide or in some cases dimethylsulfoxide/dimethyl formamide. The orthogonal peripheral handles of the resulting dendrimers are available for the eventual attachment of drugs, imaging agents or radiolabels and for the biological evaluation of these carriers. Spec. 34, ll. 6-13. Appeal 2020-004873 Application 15/277,877 6 The Examiner has advanced no persuasive evidence to support the Examiner’s contention that the teachings of the Specification would not be applicable to dendrimers other than those discussed in the disclosure. See MPEP § 2163(111). We find the Examiner erred in concluding that the disclosure of the application relied upon fails to reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date. Therefore, we reverse the rejection. Obviousness Based on Mishra Combined with Li ‘968 and Wiener The issue with respect to this rejection is whether a preponderance of the evidence supports the Examiner’s finding that the subject matter of claims 36, 37, 39-41, 45, 50, and 58 would have been obvious to one of ordinary skill in the art at the time the invention was made over Mishra combined with Li ‘968, and Wiener. The Examiner finds Mishra teaches “due to the presence of multiple surface sites on the dendrimer surface, moieties with different functionalities can be attached simultaneously and modification of functional groups on the periphery of a dendritic structure offers a convenient route to new dendrimers.” Final Act. 7. The Examiner finds Mishra teaches PAMAM dendrimers can be PEGylated to reduce the toxicity of the dendrimers. The Examiner finds Mishra does not teach a “PAMAM dendrimer with an amino acid attached to the terminal groups of the dendrimer, wherein the functional groups of the amino acid are then used to attach additional agents such as PEG or a drug.” Id. at 8. The Examiner finds Lin ‘968 teaches dendritic poly(amino acid) carriers with multiple functional groups on the surface as well as Appeal 2020-004873 Application 15/277,877 7 heterofunctional groups on the side chains for attachment of drugs or diagnostic agents. Id. at 8-9. The Examiner finds Li ‘968 teaches that the poly(amino acid) chains contain “both terminal and side chain functional groups with the side chain functional groups providing multiple points of attachment for therapeutic agents, diagnostic agents, and/or even other polymers which are attached to the functional groups on the poly(amino acid) chain by covalent or ionic interactions.” Id. The Examiner finds Li ‘968 teaches that the functional groups on the termini of the chains may be the same or different than the functional groups on the side chains. Id. at 9- 10. The Examiner concludes: It would have been obvious to the person of ordinary skill in the art at the time the invention was made to conjugate amino acids such as lysine, arginine, aspartic acid or glutamic acid onto a PAMAM dendrimer with a polymer such as PEG and a drug using the functional groups on the added amino acid as the attachment points. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Mishra discloses that surface engineering can alter the toxicity and targeting of dendrimer for drug delivery and PAMAM are among the dendrimers that have been used for drug delivery. Due to the different internal structure, PAMAMs dendrimer will have different properties that the PEI dendrimer shown in figure 1 but attachment of amino acids such as lysine or arginine results in an attached group with two additional functional groups present on the outer surface. The amino surface groups of PAMAM dendrimers will form an amide bond by reacting with the carboxylic acid of amino acids such as those shown in figure 1 while the different amino acids can provide additional functional groups. The person of ordinary skill in the art would be aware of the various chemistries and bonds such as esters and amides that can form, and these Appeal 2020-004873 Application 15/277,877 8 different bonds will not have the same cleavage rates. It would be obvious to attach a linear polymer such as PEG to the dendrimer to improve the solubility and toxicity of the dendrimer conjugate as Mishra et al. discloses that PEG can be attached to the surface of dendrimer to modify the unfavorable properties and provide an additional end group for further coupling reactions. A drug (therapeutic agent) must be included for the dendrimer to be useful as a drug delivery device and the dendrimer will not be administered neat but with additional excipients that render the dendrimer suitable for administration via routes such as those recited in claim 50. The presence of both a therapeutic agent and a targeting ligand would allow for targeted delivery of the drug payload. The size of the dendrimer (largely determined by the generation of dendrimer) determines the number of surface groups so the person of ordinary skill in the art would select the optimal dendrimer generation to use depending on factors such as the number of attachment sites needed (that are further increased by addition of amino acids such as lysine or arginine to the surface) and other factors such as the toxicity profile. Id. at 10-11. The Examiner finds that neither Mishra nor Li ‘968 teach the number of dendrimer surface groups that are reacted with the amino acids of Li ‘968. Id. at 11. The Examiner finds Wiener teaches the conjugation of 2-(4- isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (DTPA) to the primary amines of PAMAM dendrimers. Id. at 12. The Examiner finds Wiener teaches “Generation 2 and 6 dendrimers were prepared, with an average of 11 of 12 (92%) surface amine groups were functionalized for the G2 dendrimer and an average of 170 of the 192 (89%) surface amine groups were functionalized for the G6 dendrimer.” Id. Appeal 2020-004873 Application 15/277,877 9 The Examiner concludes It would have been obvious to the person of ordinary skill in the art at the time the invention was made to react a large number, e.g., 89% or 95% of the surface amine groups of the PAMAM dendrimer with an amino acid whose available functional groups are then used for further conjugation as disclosed by Mishra et al. and Li '968. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Weiner et al. discloses that a large percentage of PAMAM dendrimer surface amine groups can be reacted, resulting a single dendritic molecule that is equivalent to a large number of individual agents. Note that these amounts of Weiner et al. lie within the ranges of 59% or greater and 70 - 90% and therefore a prima facie case of obviousness exists absent evidence as to the criticality of the claimed range (see MPEP 2144.05). Alteration of the primary surface amines into more points of attachment due to the terminal and side chain functionalities of the amino acid can allow for greater surface coverage of biocompatible groups such as PEG while still providing attachment points for other agents such as drugs or diagnostic moieties, such that each dendrimer can have covalently attached a large number of therapeutic and/or diagnostic agents. Id. at 12-13. Appellant contends Mishra does not teach or suggest the claimed heterobifunctional dendrimers. Appeal Br. 21. Appellant contends that while Li ‘968 teaches dendrimers having different reactive groups, this is not the same as the dendrimers recited in the claims. Id. Appellant contends the claimed dendrimers have bifunctional linkers attached to the dendrimers as opposed to the structure of Li ‘968 which has different functional groups on the dendrimer branches. Id. at 21- 22. Appeal 2020-004873 Application 15/277,877 10 We have considered the arguments presented by the Examiner and Appellant and conclude that a preponderance of the evidence does not support the Examiner’s rejection. The present claims call for a an PAMAM dendrimer having amino acid linkers attached to the terminal functional groups of the dendrimer. Resp. To Noncompliant Brief, 4 (Claims Appx.). This structure is illustrated in Figure 1 of the present Application: Figure 1 from USSN 15/277,877 showing a schematic representation of bifunctional dendrimer and its post-functionalization in immediate Appeal 2020-004873 Application 15/277,877 11 succession annotated to show the dendrimer terminal functional groups and amino acid linkers. As recited in claim 36, after the amino acid linkers are attached to the terminal functional groups of the dendrimer, there are still two different functional groups available for attachment. Resp. To Noncompliant Brief, 4. The two remaining functional groups are chemically different. Id. For example, after attachment to the terminal functional group of the dendrimer, the amino acid linker may have a hydroxyl and an amino group available to react with another compound. Spec. 62, Table 1. In another embodiment, the linker has a thiol group and an amino group available. Id. This is in contrast with the structure taught in Li ‘968 and cited by the Examiner. Li ‘968 teaches a dendrimer having a side chain possessing the same or different functional group than the terminal functional group. Li ¶ 84. This structure is seen in Figure 8 of Li ‘968, reproduced below, were the dendrimer has carboxyl side chains: Figure 8 of Li ‘968 illustrating the structure of nonlinear PAMAM-PG8, wherein different functional groups are present at the termini of polymer Appeal 2020-004873 Application 15/277,877 12 chains (-NH2) and the side chains of branching poly(L-glutamic acid) (- COOH). As seen from the two structures the dendrimer of the present invention and that of Li ‘968 represent different approaches to providing different functional groups for attachment of different compounds. The Examiner contends that Li ‘968 teaches the addition of an amino acid linker to the terminal end of the dendrimer. Ans. 25. The Examiner contends that while the amino acids taught by Mishra and Li ‘968 would not yield a linker with two different functional groups available after conjugation to the termini of the dendrimer, one skilled in the art would know that other amino acids, such as lysine would yield such a structure. Id. at 26. We are not persuaded by the Examiner’s argument. As Appellant points out, one skilled in the art “would understand that conjugation of amino acids such as lysine and arginine would not necessarily impart two or more different external reactive chemical groups, since arginine and lysine each have only a single carboxylic acid group, and conjugation of these amino acids via the single carboxylic acid group would yield exposed amine groups (i.e., a single species of external reactive chemical group) at the surface of the dendrimers.” Rely Br. 7. Based on the foregoing we conclude that a preponderance of the evidence does not support the Examiner’s finding that the subject matter of claims 36, 37, 39-41, 45, 50, and 58 would have been obvious to one of ordinary skill in the art at the time the invention was made over Mishra combined with Li ‘968, and Wiener. Appeal 2020-004873 Application 15/277,877 13 The Remaining Obviousness Rejections Each of the remaining rejections under 35 U.S.C. § 103, rely, in part, on the teachings of Mishra, Li ‘968 and Weiner. See, e.g., Final Act. 13. As discussed above, the combination of Mishra, Li ‘968 and Wiener do not teach the dendrimer structure and amino acid linker recited in the claims. The Examiner has not pointed to any teaching in the additional references that remedies this deficiency. See, e.g., id. For this reason, we reverse the remaining rejections. CONCLUSION The Examiner’s rejections are reversed More specifically, The rejection of claims 36, 37, 39-48, 50, 51, and 58 under 35 U.S.C. §112(a) for failure to comply with the written description requirement is reversed. The rejection of claims 36, 37, 39-42, 45, 50, and 58 under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968 and Wiener is reversed. The rejection of claim 43 under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968, Wiener, and Wang is reversed. The rejection of claim 46 under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968, Wiener and Epstein is reversed. The rejection of claim 47 under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968, Wiener, and Majoros is reversed. The rejection of claims 48 and 57 under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968, Wiener, and Navath 2008 is reversed. Appeal 2020-004873 Application 15/277,877 14 The rejection of Claims 41-44 under 35 U.S.C. § 103 as unpatentable over Mishra in view of Li ‘968, Wiener, Navath 2008, Navath 2010, and Yang is reversed. The rejection of Claim 51 under 35 U.S.C. § 103 as unpatentable over over Mishra in view of Li ‘968, Wiener, Navath 2008, Navath 2010, Yang, and Li 1998 is reversed. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 36, 37, 39- 48, 50, 51, 58 112 Written Description 36, 37, 39- 48, 50, 51, 58 36, 37, 39- 42, 45, 50, 58 103 Mishra, Li ‘968, Wiener. 36, 37, 39- 42, 45, 50, 58 43 103 Mishra, Li ‘968, Wiener, Wang 43 46 103 Mishra, Li ‘968, Wiener, Epstein 46 47 103 Mishra, Li ‘968, Wiener, Majoros 47 48, 57 103 Mishra, Li ‘968, Wiener, Navath 2008 48, 57 41-44 103 Mishra, Li ‘968, Wiener, Navath 2008, Navath 2010, Yang 41-44 51 103 Mishra, Li ‘968, Wiener, Navath 2008, Navath 2010, Yang, Li 1998 51 Appeal 2020-004873 Application 15/277,877 15 Overall Outcome 36, 37, 39- 48, 50, 51, 57, 58 REVERSED