DETAILED ACTION
Applicant’s response received on 3/30/26 has been entered. Claims 1, 5, 9-12, 15-17, 20-21, 25, 29, 36-37, 44, 49, and 53 remain pending in this application. Of these, claims 5, 11, 12, 15 - 17, 20, 21, 25, 29, 36, 37, 44, 48, 49 and 53 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/29/22. Claims 1, 9, and 10 are currently under examination based on the elected species of markers- claim 1 (ii)- one or more markers from the group consisting of PTk7, CD109, SLC1IAS, ITGA3, ITGA2, BSG, DPP4, ATP1A1, FAP, VASN, IGF2R, and CD82. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Information Disclosure Statements
The information disclosure statement (IDSs) submitted on 3/30/26 has been considered. An initialed and signed copy of the IDS is attached to this Office Action.
Claim Rejections - 35 USC § 102
The rejection of pending claims 1, 9, and 10 under 35 U.S.C. 102 (a)(1)/102 (a)(2) as being anticipated by U.S. Patent Application Publication 2016/0220613 (August 4, 2016), hereafter referred to as Lim, is withdrawn in view of applicant’s arguments that mesenchymal stem cell exosomes are heterogeneous and that applicant’s mesenchymal stem cell exosomes were obtained using a substantially different method than that used by Lim where the exosomes with the claimed expression phenotype were obtained from fraction 9 of an iodixanol cushion gradient such that inherency for a 20% increase in expression of the claimed markers compared to dermal fibroblast exosomes has not been established.
Claim Rejection - 35 USC § 103
The rejection of claims 1, 7, 9 and 10 under 35 U.S.C. 103 as being unpatentable over Lim as applied to claim 1, 7 (in part), and 9 – 10 above, and further in view of Rani et al. (hereinafter referred to as “Rani”) (Rani S. et al. Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-free Therapeutic Applications. Mol Ther. 2015 May;23(5):812-823. doi: 10.1038/mt.2015.44. Epub 2015 Mar 19. PMID: 25868399; PMCID: PMC4427881), is withdrawn in view of the cancellation of claim 7, and further in view of applicant’s arguments concerning the teachings in Lim for Wharton’s Jelly derived mesenchymal stems exosomes and the lack of teachings in Rani for marker expressed in Wharton’s Jelly derived mesenchymal stems exosomes.
Double Patenting
The rejections of pending claims 1, 9, and 10 are maintained on the ground of statutory double patenting as being unpatentable over: 1) claims 1 - 14 of US Patent No. 10,624,929 B2 (issued April 21, 2020) OR 2) claims 1 - 15 of US Patent No. 9, 901,600 B2 (issued Feb. 27, 2018), are both withdrawn as statutory double patenting does not apply.
The following new rejection has been found to apply.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 9, and 10 ae rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10,624,929, hereafter referred to as the ‘929 patent, OR claims 1-18 of U.S. Patent No. 11,759,481, hereafter referred to as the ‘481 patent Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
The ‘929 patent claims recite a compositions comprising isolated exosomes with a particular protein profile, where the exosomes is isolated from a human mesenchymal stem cell, and more particularly a Wharton’s jelly mesenchymal stem cell (‘929 patent claims 1, and 5-7). The ‘929 claims are broader than the instant claims, but specifically encompass Wharton’s jelly human mesenchymal stem cell exosomes. The ‘929 patent claim exosomes further differ from the instant claims in that the claims do not recite the expression profile recited in the instant claims or that at least one of these expression markers exhibits a 20% increase in expression compared to dermal fibroblast exosomes. The ‘481 patent claims are method claims that recite the administration of isolated exosomes which are the same as those recited in the ‘929 patent claims (‘481 patent claims 1, and 10-12).
However, while the ‘929 patent claims nor the ‘481 patent claims recite the same expression markers recited in the instant claims, the specification of the ‘929 patent and the ‘481 patent each individually teach that the mesenchymal stem cell exosomes, and specifically the Wharton Jelly derived mesenchymal stem cell exosomes are prepared by banding on a 10%-60% step gradient of iodixanol by centrifugation at 100 k×g for 3.5 hours. This is the same method used in the instant specification to obtain the instant claimed exosomes. Note that the MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for obvious-type double patenting rejections. In particular, the MPEP notes that the portion of the specification that supports the patent claims may be considered. See In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). The court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003). In particular, those portions of the specification which provide support for the reference claims may be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized “that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim,” but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent or application which provides support for the claim. According to the court, one must first “determine how much of the patent disclosure pertains to the invention claimed in the patent” because only “[t]his portion of the specification supports the patent claims and may be considered.” The court pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.” In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). The MPEP gives the example that if the reference patent discloses several species within the scope of the reference genus claim, that portion of the disclosure should be analyzed to properly construe the reference patent claim and determine whether it anticipates or renders obvious the claim in the application being examined. Because that portion of the disclosure of the reference patent is an embodiment of the reference patent claim, it may be helpful in determining the full scope and obvious variations of the reference patent claim. Thus, based on a consideration of the portion of the disclosure directly related to obtaining the exosomes claimed in the ‘929 or ‘481 patent claims, it appears that the exosomes obtained and claimed by the ‘929 patent claims or the ‘481 patent claims encompass and render obvious the exosomes as currently claimed.
Claim Rejection - 35 USC § 112(b)
The rejection of pending claims 1, 9, and 10 under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention, is withdrawn in view of applicant’s amendments to the claims.
The following new grounds of rejection have been found to apply.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 9 and 10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for Wharton’s jelly mesenchymal stem cell derived exosomes isolated from fraction 9 of an iodixanol cushion gradient with a density of -1.18 g/ml, wherein the exosomes are 50-150 nm in diameter and exhibit the expression marker profile recited in claim 1 (ii), does not reasonably provide enablement for any exosome obtained from Wharton’s Jelly or bone marrow where the exosomes have the claimed protein profile. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The claims recite an isolated mesenchymal stem cell (MSC) exosome, wherein:(i) the isolated MSC exosome comprises four or more markers selected from the group consisting of Vascular endothelial growth factor receptor 1 (FLT1), Urokinase plasminogen activator surface receptor (PLAUR), Neprilysin (MME), Cadherin-2 (CDH2), Monocarboxylate transporter 4 (SLC16A3), Cadherin-13 (CDH13), Integrin beta-5 (ITGB5), Integrin alpha-11(ITGA11), Amyloid beta A4 protein (APP), Glypican-6 (GPC6), Immunoglobulin superfamily member 8 (IGSF8), Iron- responsive element-binding protein 2 (IRP2), Tetraspanin-9 (TSPAN9), Dystroglycan (DAG1), Sodium-coupled neutral amino acid transporter 2 (SLC38A2), Solute carrier family 12 member 8 (SLC12A8), Gap junction alpha-1 protein (GJA1), Integrin alpha-1 (ITGA1), Plexin-B2 (PLXNB2), Monocarboxylate transporter 1 (SLC16A1), and Endothelial protein C receptor (PROCR);(ii) the isolated MSC exosome comprises one or more markers that is enriched compared to a dermal fibroblast exosome and the same one or more markers is present in the isolated MSC exosome at a level that is at least 20% higher than the level of the one or more markers in exosomes derived from a dermal fibroblast exosome, the one or more markers selected from the group consisting of: Inactive tyrosine-protein kinase 7 (PTk7), CD 109 antigen (CD 109), Neutral amino acid transporter B(0) (SLC1A5), Integrin alpha-3 (ITGA3), Integrin alpha-2 (ITGA2), Basigin (BSG), Dipeptidyl peptidase 4 (DPP4), Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1), Prolyl endopeptidase FAP (FAP), Vasorin (VASN), Cation-independent mannose-6-phosphate receptor (IGF2R), and CD82 antigen (CD82); and/or (iii) the isolated MSC exosome comprises one or more markers that is enriched compared to a dermal fibroblast exosome and the same one or more markers is present in the isolated MSC exosome at a level that is at least 20% higher than the level of the one or more markers in exosomes derived from a dermal fibroblast exosome, the one or more markers selected from the group consisting of Reticulocalbin-1 (RCN1), Ras-related protein Rap-lb (RAP1B), Growth/differentiation factor 15 (GDF15), FLT1, Olfactomedin-like protein 3 (OLFML3), Procollagen-lysine,2-oxoglutarate 5- dioxygenase 2 (PLOD2), Proteasome subunit alpha type-4 (PSMA4), Pappalysin-1 (PAPPA), Inhibin beta A chain (INHBA), Testican-1 (SPOCK1), Heat shock protein beta-1 (HSPB1), Lysyl oxidase homolog 4 (LOXL4), DNA polymerase delta subunit 3 (POLD3), Calumenin (CALU), Insulin-like growth factor-binding protein 4 (IGFBP4), Complement C4-B (C4B), Tubulointerstitial nephritis antigen-like (TINAGL1), Extracellular sulfatase Sulf-1 (SULF1), Tropomyosin alpha-3 chain (TPM3), Neuroblast differentiation-associated protein AHNAK (AHNAK), Calreticulin (CALR), Ras-related protein R-Ras2 (RRAS2), ATP-dependent 6-phosphofructokinase, platelet type (PFKP), and Collagen alpha-1(XVI) chain (COL16A1);wherein the isolated MSC exosome is from human Wharton's Jelly or bone marrow; wherein the dermal fibroblast exosome is from human foreskin fibroblast cells; and wherein the isolated MSC exosome is formulated as a pharmaceutical composition, selected from the group consisting of an aerosol, a lyophilized powder, and an emulsion. Note that the elected species under examination has been underlined above. The specification broadly teaches exosomes obtained from mesenchymal stem cells and provides additional guidance for obtaining exosomes from mesenchymal stem cells isolated from umbilical cord Wharton’s jelly, or bone marrow. The specification teaches that Wharton’s jelly mesenchymal stem cells (WJMSCs), bone marrow mesenchymal stem cells (BMSCs), and dermal fibroblasts (HDFs) all secrete heterogeneous EVs that can be isolated by successive differential centrifugation coupled and concentrated through tangential flow filtration. In particular, the specification teaches floating concentrated (50x) conditioned media (CM) obtained from the WJMSCs or BMSCs on an iodixanol (IDX) cushion gradient of 10%-55% to purify and isolate a specific EV population referred to as fraction 9 which exhibited a density of -1.18 g/ml and which are 50-150 nm in diameter (specification, Figure 1, and pages 19 and 29-30). The specification further teaches that protein markers on the purified fraction 9 exosomes are differentially represented compared to other fractions of the MSC exosomes, or exosomes derived from other cell types (specification, pages 9-10). The specification also teaches that the purified fraction 9 exosomes are characterized by expression markers (proteins) which are present or enriched compared to exosomes from other cell types or from other fractions in the purification process, and are substantially free of non-exosomal protein (specification, pages 12 and 26). The specification, while describing the isolation of exosomes from both Wharton’s jelly MSCs and from bone marrow MSCs, only provides an analysis of plasma-membrane associated proteins in the F9 fraction of the Wharton’s jelly MSCs- see Tables 1 and 22 (referred to as WJ-MEX). Tables 1 and 2 identify as number of membrane proteins which are increased in WJ-MEX compared to exosomes from dermal fibroblasts (F-MEX). Note that Tables 1 and 3 are identical. Table 2 in particular listed a number of membrane protein which are enriched > 4 fold in WJ-MEX compared to F-MEX. These are the proteins recited as expression markers in claim 1 (ii). The specification, however, does not provide a similar analysis for the bone marrow MSC fraction 9 exosomes or for any other purification fraction from either WJ-MSC or BM-MSCs. The specification further does not teach that bone marrow MSC fraction 9 exosomes have the same protein expression profile as the Wharton’s jelly MSC fraction 9 exosomes. Thus, as the specification clearly teaches that protein markers on the purified fraction 9 exosomes are differentially represented compared to other fractions of the MSC exosomes, or exosomes derived from other cell types, and further that the fraction 9 exosomes from Wharton’s jelly MSCs are characterized by expression markers (proteins) which are present or enriched compared to exosomes from other cell types or from other fractions in the purification process, the specification fails to provide sufficient guidance for a membrane protein expression profile of bone marrow MSC derived exosomes from any purification fraction including fraction 9, or for any fraction other than fraction 9 of Wharton’s jelly MSC derived exosomes which matches the expression profile recited in the instant claims.
Turning to the state of the prior art at the time of filing, the prior art agrees with the assessment of exosome heterogeneity provided in the specification and argued by applicant in their instant response. The most recent review of the prior art for mesenchymal stem cell exosomes was published less than 2 months after applicant’s effective filing date and teaches that exosomes protein profiles are not homogenous, and that different subtypes of exosomes characterized by different marker proteins are produced by the same cells (Willis et al. (2017) Frontiers in Cardiovascular Medicine, Vol. 4, Article 63, doi:10.3389/fcvm.2017.00063, page 1-13, see pages 4-5). Willis states that recent evidence has demonstrated that mesenchymal stem cells (MSCs) release distinct subpopulations that differ in biophysical, proteomic, and RNA repertoires (Will et al., page 4). Willis et al. also teaches that the expression profile of exosomes are also influenced by cell culture conditions and the microenvironment that triggers their release (Willis et al., page 4). Willis et al. teaches that in order to develop exosome-based therapeutics, researchers should focus on the development of “label-free” exosome isolation techniques that are capable of distinguishing exosome subtypes (Willis et al., page 7). Kowal et al. further provides specific proteomic data showing the heterogeneity of exosomes from a specific cell type and between different cell types (Kowal et al. (2016) PNAS, doi/10.1073/pnas.1521230113, e968-e977). In particular, Kowal et al. shows that exosomes from different fractions, in this case, fractions 3 and 5, from an iodixanol cushion gradient centrifugation of conditioned media from dendritic cells have substantially different protein expression markers (Kowal et al., Figures 2 and 3). Thus, at the time of filing, the heterogeneity of exosomes obtained from cells was well established as was the presence of various subtypes of exosomes from the same cells with different protein profiles. Further, the state of art teaches the unpredictability of determining a priori the protein profile of any particular exosome obtained from a specific cell.
Therefore, in view of the art recognized developing understanding of the heterogeneity of exosomes, including exosomes obtained from mesenchymal stem cells, the art recognized differences in the protein profiles of exosomes from different cells, and exosomes produced by the same cell, the specific method of isolating exosomes disclosed by the specification and the specific fraction of exosomes described by the specification, the limitation of the guidance in regards to protein profiles for any mesenchymal stem cell exosome other than a fraction 9 exosome obtained from Wharton’s jelly MSCs, and the breadth of the claims, it would have required undue experimentation to make and use the breadth of isolated exosomes with the expression marker prolife recited in claim 1 (ii).
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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