Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s amendments and remarks, filed 12/23/2025, are acknowledged.
Claims 1-25, 27-28, 30-36, 39, 41, 43-52 are canceled.
Claim 26 is amended.
Claims 26, 29, 37-38, 40, and 42 are pending.
As such, claims 26, 29, 37-38, 40, and 42 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/23/2025 has been entered.
Withdrawn Rejections
The rejection of claims 26, 29, 37-38, 40, and 42 under 35 USC 103 as allegedly being unpatentable over Kalluri, Kamerkar, Skoudy, Oudin, Diersch, Costa-Silva, Brown, Nakase, is modified in favor of the new limitations added in the amendment filed 12/23/2025. Specifically, Examiner acknowledges that claim 26 was amended to recite “wherein the exosomes comprise epidermal growth factor receptor (EGFR) on their surface”. Applicant’s arguments, see pages 3-7, filed 12/23/2025, with respect to claims 26, 29, 37-38, 40, and 42 rejected under 35 USC 103 have been fully considered.
Applicant’s remarks, see page 8, filed 12/23/2025, with respect to:
claims 26, 29, 37-38, and 40 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-6, 9-12, 14-16, 32, 35-39, and 41 of copending Application No. 17/429,285 (reference application) in view of Gutkin, Kalluri as evidenced by Skoudy et al, Oudin et al, Diersch et al, Costa-Silva et al, and Brown et al;
claims 26, 29, 37-38, 40, and 42 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-6, 9-12, 14-16, 32, 35-39, and 41 of copending Application No. 17/429,285 (reference application) in view of Gutkin, Kalluri as evidenced by Skoudy et al, Oudin et al, Diersch et al, Costa-Silva et al, and Brown et al, and Nakase et al;
claims 26, 29, 37-38, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 6-7 of U.S. Patent No. 10,959,952 in view of Kalluri as evidenced by Skoudy et al, Oudin et al, Diersch et al, Costa-Silva et al, and Brown et al; and,
claims 26, 29, 37-38, 40, and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 6-7 of U.S. Patent No. 10,959,952 in view of Kalluri as evidenced by Skoudy et al, Oudin et al, Diersch et al, Costa-Silva et al, Brown et al, and Nakase et al
have been fully considered and are persuasive. Examiner acknowledges that claim 26 was amended to recite “wherein the exosomes comprise epidermal growth factor receptor (EGFR) on their surface” which is not disclosed by the ‘285 application or ‘952 patent. As such, the (provisional) double patenting rejections are withdrawn.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 42 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 42 is drawn to the method of claim 26, wherein the exosomes comprise a growth factor on their surface. It is unclear if the growth factor on the surface is different from the EGFR recited in the base claim, or if a different growth factor is on the surface.
Claim Rejections - 35 USC § 103
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.
Claims 26, 29, 37-38, 40, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Kalluri et al. (WO 2016/201323 A1, publication date: 12/15/2016; previously submitted with the action mailed 04/11/2024) as evidenced by Skoudy et al (J Gastrointest Canc (2011) 42:76–84; previously submitted with the action mailed 09/29/2024), and further in view of Adamczyk et al (Life Sciences 89 (2011) 304–312), Oudin et al. (Cold Spring Harb Symp Quant Biol 2016 81: 189-205; previously submitted with the action mailed 04/11/2024), Costa-Silva et al. (Nature Cell Biol. (2015) 17(6): 816-826; previously submitted with the action mailed 04/11/2024), and Brown et al. (WO 2014/043311 A1, publication date: 03/20/2014; previously submitted with the action mailed 04/11/2024).
With respect to instant claims 26, 29, and 42, Kalluri et al. disclose of lipid-based nanoparticles (i.e., exosomes) having CD47 on their surface and comprising a therapeutic agent (e.g., a therapeutic protein, an antibody, an inhibitory RNA, and/or a small molecule drug) (see Abstract). Kalluri et al. disclose of a pharmaceutical composition comprising a lipid-based nanoparticle having CD47 on their surface and comprising a therapeutic agent to use for a method of treating cancer (see claims 1-7 and 17-18). Particularly, Kalluri et al teach of a method of treating pancreatic ductal adenocarcinoma using exosomes comprising siRNA that targets KrasG12D in mice studies (see Example 1). Kalluri et al fail to disclose that pancreatic ductal adenocarcinoma is positive for c-Myc, however it is well established in the art that c-Myc is overexpressed in human pancreatic ductal adenocarcinoma as evidenced by Skoudy et al. Lastly, Kalluri et al disclose that the inhibitory nucleic acid (i.e., siRNA) may be any nucleic acid sequence that has been found by any source to be a validated downregulator of a protein of interest (i.e., c-Myc) (see [00148]).
While Kalluri et al is drawn to exosomes having CD47 on their surface, it is known in the art that pancreatic cancer cells express EGFR+ exosomes. In fact, Adamczyk et al discloses that pancreatic cells release 110 kDa soluble N-terminal fragment of EGFR (sEGFR) and two EGFR isoforms residing on exosomes (see pg. 305, left col; Discussion). Adamczyk et al disclose that the soluble and exosomal EGFR forms may function as an antibody decoy, and the exosomes can transfer their cargo to recipient cells in functionally active forms (see pg. 311, left col).
As such, one would be motivated to modify the method of treating cancer comprising delivering a CD47-expressed exosome comprising an inhibitory RNA with an EGFR-expressed exosome because the art teaches that pancreatic cancer secretes EGFR-positive exosomes as evidenced by Adamczyk et al. Thus, one would have a reasonable expectation that an exosome comprising a growth factor, like EGFR, on its surface/membrane would interact with the receptors on the cancer cell resulting in enhanced cellular uptake of the exosome allowing increased delivery of the therapeutic siRNA encapsulated within them.
Further, while Kalluri et al fail to disclose of a lipid-based nanoparticle comprising the sequence described in instant SEQ ID NO: 1, Brown et al. teach of compounds, compositions, and methods useful for reducing MYC target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents (see Abstract). Brown et al. teach of a method of treating a MYC-associated disease in a subject comprising administering the isolated nucleic acid and a pharmaceutically acceptable carrier to the subject in an amount sufficient to treat said MYC-associated (see claim 72). Brown et al. disclose that the MYC-associated disease is selected from the group consisting of liver, renal, breast, lung, ovarian, cervical, esophageal, oropharyngeal and pancreatic cancer (see claim 73). Brown et al. disclose that the isolated nucleic acid is formulated in a lipid nanoparticle (LNP) (see claim 54). Brown et al. disclose that the isolated nucleic acid is DsiRNA that targets MYC and the lipid nanoparticle is liposome (see Example 9; pages 41 and 42). Brown et al. disclose of a DsiRNA comprising SEQ ID NO: 2980 which shares 100% identity to the instant siRNA comprising SEQ ID NO: 1 (see alignment).
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One would be motivated to develop the claimed exosome comprising the sequence described in instant SEQ ID NO: 1 because Kalluri et al. have demonstrated a method of treating pancreatic ductal adenocarcinoma in mice models by administering an exosome comprising a siRNA that targets oncogene KrasGD. Additionally, Brown et al. have demonstrated a method of treating different cancers, including pancreatic cancer (see Example 8; pg. 390), in mice models by administering a liposome comprising a siRNA that targets c-MYC. As such, one of skill in the art would have a reasonable expectation that administering either an exosome comprising a siRNA that targets oncogenes such as KrasGD or c-MYC to a patient with pancreatic cancer would result in successful treatment for the patient.
Further, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering an exosome comprising a siRNA that targets oncogene KrasGD that treated pancreatic ductal adenocarcinoma in combination with a liposome comprising a siRNA that targets c-MYC as taught in the references above, one would achieve a method for treating pancreatic cancer, specifically pancreatic ductal adenocarcinoma.
With respect to instant claims 37 and 38, Kalluri et al. teach that the exosomes are derived from the patient’s own cells (see [0017]). Particularly, Kalluri discloses that the exosomes are derived from the patients’ samples body fluids (see [0057]).
Lastly, with respect to instant claim 40, while Kalluri et al. does not specifically disclose of a growth factor gradient at a site of the cancer to attract the lipid-based nanoparticle to the site, growth factor/chemokine/cytokine gradients are a feature of many tumors, wherein the tumor secretes growth factors into the tumor microenvironment, outside of the cancer cells themselves; thus, inherently creating a gradient as evidenced Oudin et al. Particularly, with pancreatic ductal adenocarcinomas (PDACs), Costa-Silva et al. disclose that PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells; this fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages (see Abstract). Additionally, Adamczyk et al discloses that pancreatic cells release 110 kDa soluble N-terminal fragment of EGFR (sEGFR) and two EGFR isoforms residing on exosomes (see pg. 305, left col; Discussion).
As such, the teachings of the art taken together make the present invention prima facie obvious because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. One would have been motivated to combine the teachings of the art above because it is known that pancreatic cancer cells secrete EGFR+ exosomes as well as produce a growth factor gradient as evidenced by Adamczyk, Oudin, and Costa-Silva. Thus, one would have a reasonable expectation that engineering said EGFR+ exosome to comprise an inhibitory RNA sequence that downregulates c-Myc (i.e., SEQ ID NO: 1) would treat pancreatic ductal adenocarcinoma similarly to the CD47+ exosome of Kalluri et al because c-Myc is overexpressed in human pancreatic ductal adenocarcinoma, as evidenced by Skoudy et al, and would easily interact with the receptors of the cancer cells to deliver the therapeutic inhibitory RNA.
Applicant’s Arguments
Applicant disagrees with the 103 rejection (see pages 3-7 of the Remarks filed 12/23/2025).
Applicant's claim 26 recites, "[a] method of treating pancreatic cancer in a patient in need thereof comprising administering a composition comprising exosomes comprising an inhibitory RNA that downregulates gene expression of c-Myc to the patient, thereby treating the pancreatic cancer in the patient, wherein the exosomes comprise epidermal growth factor receptor (EGFR) on their surface, and wherein the inhibitory RNA comprises an siRNA comprising SEQ ID NO: 1." The cited portions of Kalluri, Skoudy, Oudin, Costa-Silva, Diersch, and Brown, alone or in combination, fail to disclose the specific composition of claim 1 for use in a method of treating pancreatic cancer. For example, Kalluri, Skoudy, Oudin, Costa-Silva, Diersch, and Brown, alone or in combination, do not disclose a composition comprising a growth factor- or growth factor receptor-expressing exosomes comprising an inhibitory RNA that downregulates gene expression of c-Myc to the patient.
Applicant further maintains, for at least the reasons set forth at pages 6-9 of Applicant's response to the Office Action dated March 20, 2025, that Kalluri, Skoudy, Oudin, Costa-Silva, Diersch, and Brown do not render obvious Applicant's inhibitory RNA comprising an siRNA comprising SEQ ID NO: 1. A person of ordinary skill in the art (POSITA) would not be motivated to or have a reasonable expectation of success in modifying Kalluri in view of Brown to include an siRNA comprising SEQ ID NO:1. The sequence cited by the Office, SEQ ID NO: 2980, is buried within a list of nearly 4,000 distinct sequences. Brown merely provides a "laundry list" of theoretically possible target sites and inhibitory sequences derived from the MYC transcript. To arrive at the present claims, a POSITA, starting from Kalluri, would have had to: (i) decide to look to Brown for a specific cargo; and (ii) arbitrarily select SEQ ID NO: 2980 from thousands of alternatives provided in Brown, without any guidance that this specific sequence would possess the superior knock-down efficiency and in vivo efficacy demonstrated in the present application. Such a selection could only have been made with the benefit of hindsight. Furthermore, even if a POSITA were to contemplate combining the teachings of Kalluri and Brown to achieve the present claims, there would be no reasonable expectation of success. Brown concerns lipid nanoparticles, a synthetic delivery system, whereas Kalluri and the present invention concern exosomes, which are vesicles with distinct surface properties and mechanisms of cellular uptake and cargo release. A POSITA would appreciate that the efficacy of an siRNA payload is highly dependent on its delivery vehicle. There would have been no reasonable expectation that any sequence listed in the context of an LNP system would exhibit superior efficacy when delivered via an exosome.
Response to Arguments
Applicant's arguments filed 12/23/2025 have been fully considered but they are not persuasive in part.
Examiner acknowledges the amendments to claim 26. As such, the rejection has been amended to address the new limitation of “wherein the exosomes comprise epidermal growth factor receptor (EGFR) on their surface”. Specifically, the rejection no longer relies on the teachings of Diersch, Nakase, or Kamerkar. Additionally, the rejection adds the teachings of Adamczyk et al which disclose that pancreatic cells release 110 kDa soluble N-terminal fragment of EGFR (sEGFR) and two EGFR isoforms residing on exosomes (see pg. 305, left col; Discussion). Adamczyk et al disclose that the soluble and exosomal EGFR forms may function as an antibody decoy, and the exosomes can transfer their cargo to recipient cells in functionally active forms (see pg. 311, left col).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to select the specific siRNA sequence over the nearly 4,000 sequences disclosed, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, with respect to Applicant citing MPEP 2144.08, Applicant is reminded that the MPEP states “When a single prior art reference which discloses a genus encompassing the claimed species or subgenus but does not expressly disclose the particular claimed species or subgenus, Office personnel should attempt to find additional prior art to show that the differences between the prior art primary reference and the claimed invention as a whole would have been obvious… Consider the size of the prior art genus, bearing in mind that size alone cannot support an obviousness rejection. There is no absolute correlation between the size of the prior art genus and a conclusion of obviousness. See, e.g., Baird, 16 F.3d at 383, 29 USPQ2d at 1552. Thus, the mere fact that a prior art genus contains a small number of members does not create a per se rule of obviousness. Even where the genus contains a small number of members, the disclosed genus may not possess a recognizable class of compounds with common properties. This is a distinction between an obviousness rejection and an anticipation rejection. Contrast the obviousness consideration with an anticipation rejection where it is clear that each member of the small genus contains common properties.” In this particular case, Brown does explicitly disclose of the claimed inhibitory RNA. As stated in the rejection above, Brown et al teach of compounds, compositions, and methods useful for reducing MYC target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents (see Abstract). Brown et al teach of a method of treating a MYC-associated disease in a subject comprising administering the isolated nucleic acid and a pharmaceutically acceptable carrier to the subject in an amount sufficient to treat said MYC-associated (see claim 72). Brown et al disclose that the MYC-associated disease is selected from the group consisting of liver, renal, breast, lung, ovarian, cervical, esophageal, oropharyngeal and pancreatic cancer (see claim 73). Brown et al disclose that the isolated nucleic acid is formulated in a lipid nanoparticle (LNP) (see claim 54). Brown et al disclose that the isolated nucleic acid is DsiRNA that targets MYC and the lipid nanoparticle is liposome (see Example 9; pages 41 and 42). Brown et al disclose of a DsiRNA comprising SEQ ID NO: 2980 which shares 100% identity to the instant siRNA comprising SEQ ID NO: 1. Further, Brown establishes that this sequence (named MYC-1382) targets human MYC location NM_002467.4 and demonstrated significant inhibition of MYC in human A549 cells (human lung adenocarcinoma tissue cells) (see Table 9, and pages 259 and 370). Additionally, it is known in the art that this specific siRNA sequence (SEQ ID NO: 1) has been used to target myc which resulted in inhibiting progression of different cancers as evidenced by Yamaki et al (SCIENTIFIC REPORTS 3:1160 (2013) DOI: 10.1038/srep01160; previously submitted with the action mailed 09/24/2025) and Zeng et al (Journal of Hematology & Oncology (2015) 8:126; previously submitted with the action mailed 09/24/2025). As such, while Brown discloses of several MYC siRNA sequences, one would have reasonably elected the siRNA sequence comprising SEQ ID NO: 1 because the art, including Brown et al, demonstrated that this sequence has been used to target MYC in various cancers thus it would have been obvious to try the claimed siRNA sequence for treating pancreatic cancer with a reasonable expectation that the claimed siRNA sequence will demonstrate inhibitory properties. See MPEP 2143.
As such, the 103 rejection is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674