DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 16 October 2024 has been entered.
Status of Application, Amendments and/or Claims
3. Applicant’s response dated 10/16/2024 is considered and entered into record. Claims 1, 13 and 14 are amended. Claim 12 has been cancelled. Claims 1, 3, 5, 11 and 13-15 are currently pending.
4. Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10 November 2020.
5. Claims 1, 3, 11 and 13-15 drawn to a method for treating cancer comprising administering an exosome to a subject, are being considered for examination in the instant application.
Rejection withdrawn
6. Upon consideration of appropriate amendment of claim 1, the rejections under 35 U.S.C. 103 are withdrawn.
New Rejections
Claim Rejection - 35 USC § 103
7. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
8. Claims 1, 3, 11 and 13-15 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Ohno et al. (Mol Ther 21: 185-191, adv online published - October 2, 2012), Zhao et al. (Stem Cells 30: 314-325, 2012), and Kang et al. (J Proteome Res 7: 3475-3480, 2008), in view of Ishiwata et al (World J Gastroenterol 17: 409-418, 2011), in further view of Thomas et al. (Biotechnol Lett 31: 1167-1172, 2009) (IDS) and Sinden et al. (US 2015/0079046, claiming priority to GB 1205972.1, filed 4/3/2012), as evidenced by O’Loughlin et al. (Curr Gene Ther 12: 262-274, 2012) and Wangenheim et al. (J Cancer Res Clin Oncol 134: 725-741, 2008).
9. The claims are directed to a method of treating nestin-positive melanoma or breast cancer (BC) comprising administering to a subject in need thereof an exosome isolated from a conditionally immortalized neural stem cell (NSC) line, inducing differentiation of the tumor cells, and reducing the nestin expression, wherein: the exosome is loaded with exogenous mRNA or miRNA (claim 1); and the nucleic acid is coding, non-coding or regulatory (claim 3). Claim 11 recites that the exosome from the NSC: is proliferating, does not express doublecortin (DCX) or glial fibrillary acidic protein (GFAP), and/or has been cultured for less than 4 weeks or not more than one week. Claim 13 recites that the NSC line is grown in serum free medium, and claim 14 recites that the NSC line is CTX0E03. Claim 15 recites the size or density of the exosome.
10. Ohno et al teach the use of exosomes as nucleic acid drug delivery carriers in a cancer model (Introduction, para 5), and shows that “exosomes targeted to tumors may allow systemic administration of miRNA as cancer therapy” (page 189, col 2, para 2). The reference teaches that the exosomes are microvesicles of 50-100 nm in diameter, which are secreted by various cell types (Introduction, para 2), and that miRNAs or MicroRNAs are noncoding RNA molecules (Introduction, para 1). The reference also teaches the efficient delivery of microRNA in exosomes to breast cancer cells, wherein the delivery is by intravenous injection to mice having breast cancer (Abstract; page 190, col 1, para 6). Ohno et al teach that miRNA is introduced (exogenous miRNA) into the exosomes (page 189, col 1, para 1).
11. Even though Ohno et al teach modified exosomes from HEK293 cells, the reference suggests that exosomes from different cell types can be used as RNA or drug delivery carriers in cancer (Introduction, para 2, 3, 5). In considering the disclosure of a reference, it is proper to take into account not only specific teaching of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom (In re Preda, 401 F.2d 825, 159 USPQ 342, 344 (CCPA 1968)).
12. Ohno et al. do not teach a neural stem cell or NSC.
13. Zhao et al. teach that NSCs have “inherent tumor tropic properties that enable them to overcome many obstacles of drug delivery that limit effective chemotherapy strategies for breast cancer”. The reference teaches that NSC mediated drug therapy is more effective and less toxic than current chemotherapy for BC (Abstract). Using mice injected with MDA-MB-231-luc cancer cells and NSC, Zhao et al demonstrate that NSCs display migration to BC cells, and which is to a greater extent to more invasive BC cells like MDA-MB-231 (page 317, col 1, para 5; col 2, para 1; Figure 1) showing greater tropism of NSC (Figure 1C). The reference states that this “targeted therapy of breast cancer may increase the therapeutic index in patients, while minimizing toxicity to normal tissues, thus also improving quality of life” (page 324, para spanning cols 1, 2). Even though Zhao et al. do not teach that exosomes are derived from NSCs, exosomes are known to be naturally present in stem cells and neurons, which retain the “membrane topology of the parent cell”, and are valuable natural cell-derived nanocarrier for miRNA delivery, as evidenced by O’Loughlin et al (Abstract; page 263, col 1; page 264, col 1, para 2).
14. Ohno or Zhao do not teach exosomes isolated from an immortalized neural stem cell line.
15. Kang et al teach that exosomes are small membrane vesicles of 30-100 nm diameter size, which are secreted by different cell types, and play a role in different physiological functions like intercellular communication, and membrane exchange between cells (Abstract). The reference teaches that exosomes can deliver protein and mRNA (coding nucleic acid), and are useful in cancer treatment or immunotherapy (Introduction, para 1). The reference also teaches isolation of exosomes from an immortalized human neural stem cell (line) HB1.F3 (page 3476, Exptl Section: Figure 2).
16. Ohno et al, Zhao et al or Kang et al do not teach that the breast cancer is nestin positive.
17. Ishiwata et al teach that nestin is a neuronal stem cell marker and is expressed in various tumor cells including breast cancer (BC), and that the expression correlates with “aggressive growth, metastasis, and poor prognosis” (Abstract; page 410, col 1, para 2; Table 1; page 412, Nestin in Breast Cancer). The reference teaches that triple negative breast cancers have higher nestin expression, and that nestin is a selective marker for this cancer type (page 412, Nestin in Breast Cancer, para 2).
18. Ishiwata teaches that nestin expression is high in BC, and uses glioma (or glioblastoma) as an example to show that downregulation of nestin induces cell cycle arrest (page 411, col 2, para 1). Ishiwata concludes that nestin is a “novel therapeutic target” or a “molecular target for nestin-positive cancer cells” (Figure 1; Conclusion). The reference teachings, therefore, implicitly suggest that reduction of nestin expression would be an intended goal of cancer (including BC) therapy. A reference must be considered, under 35 U.S.C. 103, not only for what it expressly teaches but also for what it fairly suggests; all disclosures of prior art, including unpreferred embodiments, must be considered in determining obviousness (In re Burckel 201 USPQ 67 (CCPA 1979)).
19. Ohno et al, Zhao et al, Kang et al or Ishiwata et al do not teach exosomes isolated from a conditionally immortalized neural stem cell line like CTX0E03.
20. Thomas et al teach CTX0E03 is a therapeutic human neural stem cell line derived from 13-week gestation fetal cortex, is conditionally immortalized and is produced using a serum free culture medium (Abstract; page 1168, col 1, para 2; Conclusion). The reference teaches that the cells are proliferating (page 1170, col 1, para 2; Fig 3a) (instant claims 11a, 13, 14). The reference also teaches that the conditional immortalization of CTX0E03 makes it clonal and confers “augmented culture expansion with genetic stability” (page 1168, col 1, para 2). The reference further teaches that such stem cell lines can be used for “many unmet medical needs” (Conclusions).
21. Sinden et al (with an earlier priority date of 4/3/2012; instant application has a prior filing date of 10/9/2013) teach that exosomes can be derived (isolated) from CTX0E03, and can be used for therapy (Abstract; claims 1-6). The reference also teaches that microparticles (like exosomes) have a size of between 30 and 1000nm, 30 and 200nm or 30 and 100nm, and can comprise mRNA or miRNA (para 0010; Table 1; claims 6-8).
22. Even though Ohno et al, Zhao et al, Kang et al, Ishiwata et al, Thomas et al, or Sinden et al do not teach “inducing differentiation of tumor cells… and reducing nestin expression…” (claim 1), upon considering the broadest reasonable interpretation (BRI) of the claim, these limitations are not steps that are actively performed by the artisan, but rather they to pertain to a necessary outcome of the step of administering a cancer therapeutic (in this case comprising an exosome loaded with nucleic acid). It is noted that the instant specification (page 5, line 17) teaches that “a more differentiated tumour typically correlates with improved prognosis” (emphasis added), indicating that tumor cell differentiation is a result that is desired and expected after administering cancer therapeutics. Moreover, as evidenced in the relevant prior art (Wangenheim et al.; submitted with the last office action), inducing differentiation in cancer cells is a therapeutic strategy (page 736, col 2, last para), and antitumor drugs demonstrating this feature are proven to be clinically important (page 732, col 1, para 1), emphasizing that administering a component for treating cancer would necessarily induce differentiation of tumor cells. Therefore, upon performing the step of administering an exosome loaded with exogenous mRNA or miRNA to a subject having nestin-positive cancer (breast cancer), for treating said cancer, one will necessarily have induced differentiation of tumor cells followed by reducing nestin expression of the cancer being treated. As such, based upon the BRI of claim 1, the “inducing” clause is merely a result that follows the active step of administration, since there is no requirement for an actual action to manifest “inducing differentiation” or “reducing expression”, for example detecting differentiation and reduced nestin expression. An as the combined prior art provides for treating nestin-positive cancer by administering exosomes loaded with exogenous nucleic acid (mRNA or miRNA), reduced nestin expression would necessarily be present along with induced differentiation of tumor cells, absent evidence to the contrary.
23. It therefore would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method for treating breast cancer using exosomes loaded with nucleic acid, wherein the exosomes are derived or isolated from neural stem cells/neural stem cell line based upon Ohno et al, Zhou et al and Kang et al, wherein the breast cancer is nestin positive as taught by Ishiwata et al, by using exosomes derived from a conditionally immortalized neural stem cell line CTX0E03 in view of the teachings of Thomas et al and Sinden et al. The person of ordinary skill would have been motivated to use neural stem cells for treating BC as these cells demonstrate greater tropism and migration to BC cells, thereby increasing the therapeutic index in patients, while minimizing toxicity to normal tissues, along with improving quality of life (Zhao et al). The person of ordinary skill would likewise be motivated to use exosomes from neural stem cells as these can deliver mRNA therapeutics, and are useful in cancer treatment (Kang et al). The person of ordinary skill would also be motivated to treat BC which is nestin-positive by reducing nestin expression, as nestin is a selective marker for breast cancer and its expression correlates with aggressive growth of cancer (Ishiwata et al). The person of ordinary skill would further have been motivated to use CTX0E03 neural stem cell line, as it is from humans, is conditionally immortalized, has been shown to be therapeutic and achieves “scalable and reproducible manufacture of cell-based therapies” (Thomas et al, Abstract). The person of ordinary skill would have expected success because neural stem cells migrate to breast cancer cells, and exosomes from different cell types were investigated as delivery vehicles for breast cancer treatment, before the effective filing date of the instant invention.
24. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
Applicant’s Remarks
25. Alleging nonobviousness over the cited art, and asserting advantages of a conditionally immortalized cell line as the source of exosome for therapeutic administration, Applicant argues that the knowledge of "CTX0E03 exosomes did not exist in the art" "prior to the effective filing date of the instant application", even though these cells were "very well characterized and were being studied in clinical trials". Applicant adds that neither Thomas, nor any of the cited references provide any suggestion to try isolating exosomes from this cell line. Applicant further emphasizes that the "lack of identified exosomes from a cell line as well characterized as CTX0E03 would cause the skilled person to consider that these cells did not produce exosomes". Applicant alleges impermissible hindsight reasoning to conclude that exosomes are isolated from conditionally immortalized NSCs, as this “was not known or contemplated until several years after the publication of Thomas”.
26. Applicant argues that at the time of the present application (2013 priority date), the “understanding of the field of exosomes was much less developed….and was characterized by uncertainty”. Providing Kang’s example, Applicant alleges that “Kang only exemplifies exosome isolation from the one cell type of an immortalized human neural stem cell HB1.F3”, however, does not teach or suggest other NSCs “that are not immortalized through a retroviral vector encoding v-myc, as in the HB1.F3 cells”.
27. Applicant alleges that the cited references do not teach or suggest the claimed elements. Applicant also argues that Wangenheim teachings do not relate to exosomes isolated from a conditionally immortalized NSC line. Concluding that the claims are not obvious over any combination of the references, Applicant requests withdrawal of the rejection.
28. Addressing the newly added limitation “reducing nestin expression…” in claim 1, Applicant asserts that the limitations “administering”, “inducing” and “reducing” describe “a separate action that must be actively performed, and not merely an intended result or inherent characteristic”. Applicant cites case law for support, and concludes that the absence of teaching or suggestion of the “reducing” step, “constitutes an additional reason for the patentability” of instant claims over the cited art. Applicant therefore, believes that the pending claims are in condition for allowance.
29. Applicant’s arguments are fully considered, however are not found to be persuasive. As stated above, upon consideration of present amendment all previous rejections are withdrawn and a new 103 rejection has been set forth. Applicant’s arguments to individual references are responded below.
30. Applicant’s argument that Thomas does not teach isolation of exosomes from conditionally immortalized CTX0E03 cells is accepted. However, based upon the newly added prior art (Sinden et al), it was understood that microparticles like exosomes having similar size ranges as instantly claimed could be derived or isolated from CTX0E03, and can be used for therapy. Therefore, contrary to Applicant's allegation, the knowledge of the presence of exosomes in CTX0E03 cells and its isolation therefrom was known to the person of ordinary skill in the art before the effective filing date of the instant application. For the same reasons, Applicant’s allegation of impermissible hindsight reasoning is not persuasive as the knowledge was explicitly available to the skilled person of art at the time of filing of the instant invention.
31. Applicant’s arguments that Kang only teaches exosome isolation from one immortalized NSC are not found to be persuasive. The fact that Kang states that "exosomes are secreted by a multitude of cell types" (Abstract), and exemplifies isolation from one such cell type - immortalized human neural stem cell HB1.F3, drives home that Kang establishes that exosomes are not only present in many cell types, the process of isolation of exosomes from a human neural stem cell line was also accomplished prior to the effective filing date of the instant invention. Kang certainly does not teach away the presence or isolation of exosomes from any other cell or neural cell type. It is also noted that Kang (2008) is one year prior to Thomas (2009). While Kang uses methods including the flow field-flow fractionation (FIFFF) to obtain exosomes from cells and stem cells, Thomas teaches the production of CTX0E03. That is the knowledge of obtaining exosomes from stem cells was already known at the time of the production of CTX0E03.
32. Applicant’s argument that Kang does not teach immortalization of other NSCs without the use of a retroviral vector, is not found to be persuasive. Applicant seems to be arguing a method of immortalization without using a retroviral vector. Please note that the instant claims neither are directed to a method of obtaining immortalized NSCs, nor mention a retroviral vector. Since the pending claims must be interpreted as broadly as their terms reasonably allow, Applicant is reminded that the claims define the subject matter of his invention.
33. Applicant’s argument about Wangenheim not teaching exosomes is not found to be persuasive, as the reference was not used for this purpose. Wangenheim was only used to show that cancer being a cell differentiation disease, the induction of differentiation in cancer cells would necessarily provide a therapeutic measure for the disease. Exosomes were taught by other cited references (Ohno et al, Kang et al, Thomas et al). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Please note that the Wangenheim reference is relied upon only as an evidentiary reference in the present rejection.
34. With regards to Applicant asserting that the limitations “administering”, “inducing” and “reducing” describe “a separate action that must be performed, and not merely an intended result or inherent outcome”, is considered, however, is only found to be persuasive in part. While “administering” is acknowledged as an action involving step, the “inducing” and “reducing” steps do not apparently require “a separate action” to be performed for reasons stated in the rejection above. The claims do not provide active steps to “perform” and accomplish “inducing differentiation…” and “reducing nestin expression…”. As the combined prior art teaches treating nestin-positive cancer by administering exosomes loaded with exogenous nucleic acid (mRNA or miRNA), reduced nestin expression would necessarily be present with induced differentiation of tumor cells, absent evidence to the contrary. The Examiner takes no issue with Applicant cited case law.
35. For above reasoning, the pending claims are found to be prima facie obvious over the combined teachings of the prior art, and therefore, are not yet in condition for allowance.
Double Patenting
36. 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).
37. 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).
38. 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.
39. 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.
40. Claims 1, 3, 11, and 13-15 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 22 and 23 of co-pending application number 17/785,801, in view of Ishiwata et al and Thomas et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because in each case the claims are directed to a method of administering an exosome loaded with an exogenous nucleic acid (claim 19 of ‘801 application) to a target cell like a cancer cell (canceled limitation of claim 22 of the ‘801 application), wherein the miRNA is present in exosomes in a neural stem cell like CTX0E03 cell (conditionally immortalized cell) (see claims 17 and 18 of ‘801 application), and is for use in therapy or treatment (see claim 25 of ‘801 application).
The only differences between the two sets of claims are:
(i) Instant claims recite nestin positive melanoma or breast cancer, while the ‘801 claims do not have this limitation. However, this would be obvious in view of Ishiwata et al teaching that nestin is neuronal stem cell marker of tumor cells including breast cancer. (ii) Instant claims recite “inducing differentiation…and reducing nestin expression…”, while ‘801 claims do not have this limitation. However, as stated in the 103 rejection above (para 22), this would be an obvious outcome that is intended to follow upon performing the administration step.
41. This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
42. No claims are allowed.
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/A. D./
Examiner, Art Unit 1675
12 December 2025
/KIMBERLY BALLARD/
Primary Examiner, Art Unit 1675