DETAILED ACTION
Status of the Application
Claims 36-38 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s remarks as submitted in a communication filed on 7/7/2026 is acknowledged.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Specification
The objection to the first paragraph of the specification for not providing the current status of related applications is hereby withdrawn by virtue of Applicant’s amendments.
The objection to the title of the invention for not being descriptive is hereby withdrawn by virtue of Applicant’s amendment.
Claim Rejections - 35 USC § 103 (AIA )
Claims 36-38 remain rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. (US Publication No. 2015/0342883 published 12/3/2015; cited in the IDS) as evidenced by Lin et al. (GenBank accession number P38567, 11/30/2016; 11/30/2016; cited in the IDS) in view of Johnsen et al. (Biochimica et Biophysica Acta 1846:75-87, 2014; cited in the IDS), Cherr et al. (Matrix Biology 20:515-525, 2001; cited in the IDS), and Ashiru et al. (Biochem. J. 454:295-302, 2013; cited in the IDS).
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that none of the cited references teach, suggest or provide a reasonable expectation of success that a recombinant exosome presenting a hyaluronidase on its outer surface could itself be useful as an anticancer agent. Applicant states that Cheng et al. teach an auxiliary role for hyaluronidase to promote uptake and efficacy of a separate anticancer drug that is encapsulated inside its nanoparticles. Applicant states that the pending claims recite that the recombinant exosome does not encapsulate any anticancer agents within its inner space and does not present any other exogenous compound on its outer surface. Applicant is of the opinion that Cheng et al. do not teach or suggest that degradation of extracellular matrix around cancer tissue would itself provide some therapeutic effect. Applicant refers to Figures 5A, 5B, 13C-13E in support of the argument that Cheng et al. do not show that nanoparticles that do not have anticancer agents have an anticancer effect. Applicant further submits that Johnsen et al. teach exosomes as drug delivery vehicles for therapeutic agents carried as cargo and do not teach or provide a reasonable expectation that the recombinant exosomes of the claims would be useful or effective in a method as claimed. Applicant submits that the rejection wrongly minimizes significant differences between the anticancer constructs of Cheng et al. and the claimed constructs, and the extensive modifications that would be required to modify an empty nanoparticle of Cheng et al. to arrive at the claimed invention. Applicant states that Cheng et al. teach that not all the embodiments of Cheng et al. require a cellular membrane or coating with exosomes, citing Example 2 of Cheng et al.. According to Applicant, the record provides no evidence for the assertion that the production of recombinant exosomes is a simpler method to produce a delivery system because all that is required is to genetically modify a host cell that would normally produce exosomes so that it can express the desired hyaluronidase and recover the exosomes from the culture. According to Applicant, the assertions of page 6 of the prior Office action do not provide any reason to modify Cheng et al. by replacing its nanoparticles with exosomes. Applicant refers to Figures 4C-4D, 7A-7B and 8A-8B in support of the argument that the invention provides unexpected results. Applicant submits that exosomes that do not encapsulate any anticancer agents within its inner space and do not have other exogenous compounds on their surface have a prominent anticancer effect. Applicant states that recombinant exosomes as claimed showed more anticancer activity than exosomes that encapsulated doxorubicin.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the teachings of the specification and the prior art. However, the Examiner disagrees with Applicant’s contention that the claimed invention is not obvious.
With regard to the argument that Cheng et al. teach an auxiliary role for hyaluronidase to promote uptake and efficacy of a separate anticancer drug that is encapsulated inside its nanoparticles and that Cheng et al. do not teach or suggest that degradation of extracellular matrix around cancer tissue would itself provide some therapeutic effect, Applicant’s attention is directed to the Abstract of Cheng et al. reproduced below for the reader’s convenience.
A delivery system comprising an organic nanoparticle, a hyaluronidase anchored or conjugated to the organic nanoparticle. The organic nanoparticle may be selected from a polymer-based nanoparticle, a lipid-based nanoparticle and nanoparticle formed by lipid-like molecules. In some embodiments, the hyaluronidase is covalently bound to a linker or spacer which, in turn, is anchored or covalently bound to the organic nanoparticle. The delivery system may also comprise an active pharmaceutical agent, a diagnostic agent, and/or a cellular membrane. The organic nanoparticle may further have a low density poly(ethylene glycol) layer on the surface. Methods for using the delivery system including for treating or diagnosing a disease are also provided. The organic nanoparticle provides enhanced diffusion/penetration through the extracellular matrix found in tumors, as well as increased circulation time in a human or animal body.
As indicated above, Cheng et al. specifically teach that (i) their hyaluronidase-containing nanoparticles may also comprise an active pharmaceutical agent (Abstract), and (ii) the hyaluronidase-containing nanoparticle provides enhanced diffusion/penetration through the extracellular matrix found in tumors as well as increased circulation time in a human or animal body (Abstract). In addition, as previously indicated, Cheng et al. specifically teach that their hyaluronidase-containing nanoparticle provides a therapeutic delivery system that transports hyaluronidase to a tissue, where the hyaluronidase digests the hyaluronan or hyaluronic acid in the extracellular matrix of the tissue to improve diffusion of nanoparticles or nanomedicine into the tissue (page 2, left column, paragraph [0019]). Therefore, it is abundantly clear that Cheng et al. teach both a hyaluronidase-containing nanoparticle having no additional pharmaceutical agent as well as hyaluronidase-containing nanoparticle having an additional pharmaceutical agent. The teachings of Cheng et al. clearly show that the hyaluronidase-containing organic nanoparticles of Cheng et al. without any additional active pharmaceutical agent are by themselves a biologically active compound with therapeutic use in cancer treatment by virtue of the fact that Cheng et al. teach that their nanoparticles allow the delivery of a hyaluronidase to a tissue, where the hyaluronidase digests the hyaluronan or hyaluronic acid in the extracellular matrix of the targeted tissue, thus providing enhanced diffusion/penetration through the extracellular matrix found in tumors. Cheng et al. teach that the administration of free hyaluronidase prior to the administration of anticancer agents to deplete hyaluronic acid in tumors is known in the art and that the use of conjugated hyaluronidase is beneficial because it only degrades hyaluronic acid along the path of nanoparticle diffusion, thus reducing potential side effects (page 12, paragraph [0150]). It is the hyaluronidase on the nanoparticle, and not the additional pharmaceutical agent, that is responsible for the digestion of the hyaluronan or hyaluronic acid in the extracellular matrix of the targeted tissue. Therefore, contrary to Applicant’s assertions, Cheng et al. specifically teach that degradation of extracellular matrix around tumors would itself provide some therapeutic effect.
With regard to the teachings of Figures 5A, 5B, 13C-13E of Cheng et al. and the argument that Cheng et al. do not show that nanoparticles that do not have anticancer agents have an anticancer effect, it is noted that while it is agreed that Cheng et al. do not provide data related to tumor size as a function of time after the administration of a hyaluronidase-containing nanoparticle, none of the cited figures show or suggest that hyaluronidase-containing nanoparticles do not digest hyaluronan or hyaluronic acid in the extracellular matrix of tumors. Therefore, one of skill in the art did not need to know the effect of hyaluronidase-containing nanoparticles on tumor size to be motivated to use hyaluronidase-containing nanoparticles in a method of treating cancer as Cheng et al. clearly teaches that hyaluronidase-containing nanoparticles enhance diffusion/penetration through the extracellular matrix found in tumors. It should also be noted that Figures 5A-5B do not show the effect of hyaluronidase-containing nanoparticles on tumor size but rather cell viability. Also, it is noted that Figure 13D of Cheng et al. cannot show a discernable reduction in tumor size because that figure only shows tumors at a single time point, namely 24 hours after administration of the hyaluronidase-containing nanoparticles. In order to make any conclusion regarding the effect of the nanoparticles on tumor size, one would require data for at least two time points. Therefore, contrary to Applicant’s assertions, one cannot reasonably conclude that Figure 13D shows no discernable reduction in tumor size.
With regard to the argument that Johnsen et al. teach exosomes as drug delivery vehicles for therapeutic agents carried as cargo and do not teach or provide a reasonable expectation that the recombinant exosomes of the claims would be useful or effective in a method as claimed, Applicant is reminded that the instant rejection is an obviousness rejection which is based on the combined teachings of the references cited. In the instant case, the claimed method simply requires (i) an exosome that has an inner and outer surface, wherein the exosome presents the hyaluronidase of SEQ ID NO: 1 on its outer surface, wherein the exosome lacks additional anticancer agents within its inner space and does not present other exogenous compounds on its outer surface, and (ii) a use for the treatment of cancer. As extensive discussed above and the prior Office action, hyaluronidase and hyaluronidase-containing nanoparticles have a use in the treatment of cancer in view of the teachings of Cheng et al. who disclose that this enzyme digests hyaluronan or hyaluronic acid in the extracellular matrix of tumors, thus providing enhanced diffusion/penetration through the extracellular matrix found in tumors. It is reiterated herein that to achieve this enhanced diffusion/penetration through the extracellular matrix, an anticancer agent is not required. Therefore, the issue in the instant case is whether a recombinant exosome as claimed is obvious, whether there is motivation to make recombinant exosomes as required by the claims, and whether there was a reasonable expectation of success at making such exosome and use it in a method as claimed.
As previously indicated, hyaluronidase-containing nanoparticles are therapeutic agents due to their effect on the extracellular matrix of tumors. It is reiterated herein that Johnsen et al. teach that exosomes are nanoparticles with a diameter in the range of 30-120 nm which are secreted by most cell types of the body (page 76, left column, Introduction). Johnsen et al. also teach that using exosomes as drug delivery systems has improved disease conditions, including studies performed on different cancer models (page 77, right column, last paragraph). Johnsen et al. teach the use of exosomes that have been genetically modified to produce proteins on the surface of the exosome for therapeutic purposes and provides a description of how to make exosomes by genetic engineering of murine melanoma cells to induce overexpression of the therapeutic agent (MHC-II protein) on the surface of the exosome as well as the use of these exosomes to target T-cells to elicit a potent Th1 response against cancer cells (page 82, left column, first full paragraph). One of skill in the art would have been highly motivated to use exosomes as nanoparticles to deliver the hyaluronidse of Cheng et al. (SEQ ID NO: 1) in a method as claimed because (i) Johnsen et al. teach that exosomes are small vesicles that can act as delivery systems to successfully deliver therapeutic agents to cells, and (ii) it would be easier to produce exosomes that already contain the hyaluronidase of Cheng et al. linked to the exosome’s surface than producing nanoparticles that would have to be treated to link the hyaluronidase to the nanoparticle.
While it is agreed that there was no absolute certainty that exosomes that have the hyaluronidase of Cheng et al. on the surface could be made and used in a method as claimed, it is noted that an obviousness analysis only requires a reasonable expectation of success and not absolute certainty. In the instant case, the molecular biology techniques required to make an exosome as recited were known in the art as evidenced by Johnsen et al., and the evidence by Cheng et al. and Johnsen et al. would strongly suggest to one of skill in the art that it is more likely than not that an exosome, which is also a nanoparticle, having a hyaluronidase on its surface would be able to digest the hyaluronan or hyaluronic acid in the extracellular matrix of the targeted tumor tissue.
With regard to the argument that the rejection wrongly minimizes significant differences between the anticancer constructs of Cheng et al. and the claimed constructs, and that not all the embodiments of Cheng et al. require a cellular membrane or coating with exosomes, citing Example 2 of Cheng et al., it is noted that the Examiner (i) has clearly indicated what is present or absent in the nanoparticles of Cheng et al. as it relates to the recited recombinant exosomes, (ii) has provided a reference by Johnsen et al. that teaches exosomes, which are nanoparticles, their therapeutic use, and how to make them, (iii) has provided a reasoned statement as to why one of skill in the art would have been motivated to combine the teachings of Cheng et al. and Johnsen et al. and arrive to the recited exosomes and claimed method, and (iv) has not indicated that all of the nanoparticles of Cheng et al. are partially or completely coated with a cellular membrane. The Examiner acknowledges Example 2. However, the Examiner previously indicated that Cheng et al. teach organic nanoparticles that are lipid-based nanoparticles derived from membranes and liposomes, including exosomes (page 6, paragraphs [0094]-[0096]), as well as nanoparticles coated with cellular membrane, wherein the cellular membrane is derived from an exosome (page 11, paragraph [0142]). This is not a statement indicating that the only nanoparticles taught by Cheng et al. are those partially or completely coated with a cellular membrane. Instead, the Examiner simply provided one of the embodiments taught by Cheng et al. with regard to their nanoparticles that is pertinent to the instant rejection.
With regard to the argument that the record provides no evidence for the assertion that the production of recombinant exosomes is a simpler method to produce a delivery system because all that is required is to genetically modify a host cell that would normally produce exosomes so that it can express the desired hyaluronidase and recover the exosomes from the culture, and that the assertions of page 6 of the prior Office action do not provide any reason to modify Cheng et al. by replacing its nanoparticles with exosomes, it is noted that as set forth in MPEP § 2143(G), the Courts have made clear that the teaching, suggestion, or motivation test is flexible and an explicit suggestion to combine the prior art is not necessary. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved.
In the instant case, contrary to Applicant’s assertions, the Examiner provided a reasoned statement as to why one of skill in the art would have been motivated to replace the nanoparticles of Cheng et al. with exosomes. As previously indicated, a person of ordinary skill in the art is motivated to use an exosome as recited in the claims in a method for treating cancer because (i) the prior art as evidenced by Johnsen et al. teach that exosomes are nanoparticles which are small vesicles that can act as delivery systems to successfully deliver therapeutic agents to cells, (ii) the prior art as evidenced by Cheng et al. teach that hyaluronidase attached to the surface of a particle is more effective in digesting HA in tumors, and (iii) it would be easier to produce exosomes that already contain the hyaluronidase of Cheng et al. linked to the exosome’s outer surface than producing nanoparticles that would have to be covered with exosomes and then further treated to link the hyaluronidase to the nanoparticle. The production of recombinant exosomes is a simpler method to produce a delivery system because all that is required is to genetically modify a host cell that would normally produce exosomes so that it can express the desired hyaluronidase, and recover the exosomes from the culture medium. The nanoparticles of Cheng et al., on the other hand, would require the production of exosomes, coating the nanoparticles with the exosomes, producing the hyaluronidase, and attaching the hyaluronidase to the surface of the exosome-covered nanoparticle. These recombinant exosomes that comprise the PH20 protein of SEQ ID NO: 1 can be used in any application that requires the degradative activity of a hyaluronidase on extracellular matrix tissue, particularly in a method for treating cancer in view of the teachings of Cheng et al. who disclose that hyaluronidase is usually administered for treating cancer patients to deplete hyaluronic acid (HA) from tumors prior to the administration of other anti-cancer agents. A person of ordinary skill in the art is motivated to anchor/conjugate an anticancer agent to the exosome that produces the PH20 protein of SEQ ID NO: 1 on its surface for the benefit of delivering the hyaluronidase to the cancerous tissue, where the hyaluronidase can digest the hyaluronan or hyaluronic acid in the extracellular matrix of the tissue and improve diffusion of an anticancer agent, as taught by Cheng et al. (page 2, paragraph [0019]). Since the PH20 is a GPI anchored protein as evidenced by Cherr et al., it will be recruited to exosomes as evidenced by Ashiru et al.
With regard to Figures 4C-4D, 7A-7B and 8A-8B of the specification and the argument that the invention provides unexpected results, namely a prominent anticancer effect, including more anticancer activity than exosomes that have encapsulated doxorubicin, the Examiner acknowledges the reduction in tumor size observed when exosomes that comprise the hyaluronidase of SEQ ID NO: 1 and lack other anticancer agents are used. However, it is noted that one of skill in the art did not need to know that the recited exosomes can reduce tumor size to be motivated to combine the teachings of the prior art to arrive at the claimed invention because the prior art as evidenced by Cheng et al. teach that hyaluronidase attached to the surface of a particle is more effective in digesting HA in tumors, and the prior art as evidenced by Johnsen et al. teach that exosomes are nanoparticles which are small vesicles that can act as delivery systems to successfully deliver therapeutic agents to cells. It should also be noted that Figure 8A of the specification discloses that the highest reduction in tumor volume is obtained with an exosome that comprises doxorubicin and PH20 (the polypeptide of SEQ ID NO: 1). Therefore, for the reasons of record and those set forth above, one of skill in the art would have to conclude that the claimed invention is obvious over the prior art of record.
Conclusion
No claim is in condition for allowance.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Applicant is advised that any Internet email communication by the Examiner has to be authorized by Applicant in written form. See MPEP § 502.03 (II). Without a written authorization by Applicant in place, the USPTO will not respond via Internet email to any Internet correspondence which contains information subject to the confidentiality requirement as set forth in 35 U.S.C. 122. Sample written authorization language can be found in MPEP § 502.03 (II). An Authorization for Internet Communications in a Patent Application or Request to Withdraw Authorization for Internet Communications form (SB/439) can be found at https://www.uspto.gov/patent/forms/ forms-patent-applications-filed-or-after-september-16-2012, which can be electronically filed.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
September 28, 2026
Prosecution Insights