DETAILED ACTION
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 .
Claims 1-16, 19-21, 25-26, 28-66, and 68 are cancelled.
Claims 17-18, 22-24, 27, 67, and 69-72 are pending and under examination on the merits.
Withdrawn Claim Rejections
The rejection of the claims under 35 USC § 103 recorded in the office action dated 02/21/2025 are withdrawn and replaced with the rejections presented, below, in this Office Action to account for the new claim amendments introduced by Applicant on 06/13/2025.
Newly Necessitated Claim Rejections
Claim Rejections - 35 USC § 112
35 USC § 112(a)
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.
Claim 17-18, 22-24, 27, 67, and 69-72 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The instant Application recites cells for transfection but does not further limit said recitation by way of a closed or limiting definition of what types of cells would be encompassed by said recitation. No conserved structure or function is indicated as required to function in the method as claimed. Therefore, in view of this disclosure, Applicant is claiming a broad genus of cells without a representative number of species of said genus’. The specification does not provide adequate written description for the entire claimed genus of species of cells recited in instant claim 17 and its dependents, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which cell types encompassed by the genus would function as claimed in the method.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has only disclosed transfection of 293T (HEK293) cells for consideration. Thus, given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of no species is not sufficiently representative of the entire genus.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of cells with the capacity to function as claimed in the recited method(s), because the instant specification does not provide structural features that correlate with a functional ability to function in the claimed method(s). To elaborate on why the claimed genus of cells (encompassing all cell types, from any species) lack adequate written description, Chen et al (Recent advances in scalable exosome production: Challenges and innovations, obtained from https://doi.org/10.1016/j.cjprs.2025.05.001 (available May 2025)) teach that a limited number of cells have been validated and suggested by the state of the prior art as compatible for exosome-production (such as mesenchymal stem cells, dendritic cells, human embryonic kidney 293 (HEK293) cells, tumor cell-derived exosomes, and neural stem cells (see for example Figure 1 and its caption at pg. 2)
Absent a description of the at least minimal structural features correlating with a functional ability to function in the claimed method(s) which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which cells would possess the ability to function as claimed.
Furthermore, while the prior art teaches some understanding of the production of exosomes, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences transfection of different/arbitrary cell types with respect to exosome production. Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which cells may be transfected so as to be capable of functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics that correlate with the ability to function as claimed, and because the one disclosed species detailed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The claims require transfection of cells for production of exosomes to be use therapeutically. The specification does not describe which cells may be used for the functions claimed. Rather, the specification only describes transfection of 293T/HEK293 (see for example paragraph 0138). The specification further fails to disclose the structures common to all members of the genus of cells encompassed by the broad genus claimed by Applicant which would be responsible for/make possible the claimed functions. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of cells that would function in the method(s) as claimed, but rather has presented the public with suggestion to experiment to discover which cells may or may not function in the claimed method(s). The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.”
Applicant is further directed to In re Alonso (545 F.3d 1015 (Fed. Cir. 2008), which involved claims that were directed to methods of using antibodies wherein the court found that the claims lacked adequate written description for the recited genus of antibodies recited in the methods. (C) See p. 8, 3rd paragraph, where Applicant argues that the claims recite all essential features of the invention. Thereby, products used in methods are rightfully subject to the written description requirement.
Thereby, the cells for transfection, as claimed are only disclosed by function, without a representative number of species or unifying, conserved structure enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed in the claimed method(s). Therefore, the claim 17 and its dependents, claims 18, 22-24, 27, 67, and 69-72, are deemed to fail to meet the written description requirement, as presently drafted.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 17, 18, 22-24, 27, and 69-70 are rejected under 35 U.S.C. 103 as being unpatentable over Aspeslagh et al (Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016 Jan;52:50-66. doi: 10.1016/j.ejca.2015.08.021. Epub 2015 Nov 30) in view of Johnsen et al (A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. Biochem Biophys Acta. 2014 Aug;1846(1):75-87. doi: 10.1016/j.bbcan.2014.04.005. Epub 2014 Apr 18) and Alvarez-Erviti et al (Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29, 341–345 (2011); as cited on the 01/27/2021 IDS).
Regarding claims 17, 18, 22-24, 27, and 69-70, Aspeslagh et al teach that immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumour immune responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade –based monotherapy and many others will eventually relapse. Therefore, new immunostimulatory targets are needed to overcome primary and secondary resistance to immunotherapy. Aspeslagh et al go on to teach that, besides the B7 co-inhibitory receptors, the tumour necrosis factor receptor superfamily contains many other immune checkpoints, which could become the next generation immunomodulators. Among them stands OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells. Several anti-OX40 agonistic monoclonal antibodies are currently being tested in early phase cancer clinical trials (see abstract of Aspeslagh et al). Adaptive immunity relies on the specific recognition of antigens (mostly peptides) presented by major histo-compatibility (MHC) molecules expressed at the surface of antigen presenting cells (APCs) to the T-cell receptor (TCR). This is the first step required for T-cell activation. However, for a full blown T-cell triggering, the first MHC/TCR signal requires the involvement of co-stimulatory molecules of the B7 family (that can be further dampened by signalling through co-inhibitory receptors expressed on T-cells (such as CTLA4 or PD1)). OX40 has only one known ligand called OX40L (CD252), which is classically expressed on activated antigen-resenting cells (APCs). Upon OX40 costimulation of T-cells, intra-cytoplasmic pathways associated with T-cell signalling are activated such as nuclear factor (NF)-kappaB and Nuclear factor of activated T-cells (NFAT) which can enhance the expression of molecules such as survivin, cyclin A, cyclin-dependent kinases, Bcl-2 anti-apoptotic molecules, cytokines, and cytokine receptors (see section 2 of Aspeslagh et al). OX40 expression on tumour infiltrating lymphocytes (TILs) has been studied in different tumour settings, such as breast cancer, melanoma, B-cell lymphoma and head and neck cancer. In colon cancer, high expression of OX40 on TILs, in mesenteric lymph nodes or in invasive margin lymphoid aggregates correlated with better overall survival. In lymphoma, OX40 expression was dramatically increased in CD4 T-cells, more specifically in Tregs TILs for whom OX40 expression could in fact be used as a marker of tumour antigen-specific Tregs (see section 4). Note that effects of OX40 stimulation taught in table 1 of Aspeslagh et al. In vitro experiments show that anti-OX40 will enhance CD4 and CD8 survival (see Figure 2). Interestingly, in contrast to anti-OX40 antibodies, OX40L-Fc also activated DCs and vascular endothelial cells within the tumour bed in a T-cell independent manner (see section 5; see also table 2 of Aspeslagh et al).
Anti-OX40 and OX40L-Fc therapy show a strong effect in mice bearing small tumours. However, the efficacy against more bulky tumours or metastases, a situation, which is much closer to the status of cancer patients, is less impressive. Hence, different modalities of treatment combinations have been attempted to overcome resistance to anti-OX40 molecules. In order to strengthen anti-OX40 therapy, three strategies have proved to be successful: (1) increasing antigen release (through surgery, radiotherapy, chemotherapy and vaccination), (2) adoptive T-cell therapy and (3) tackling immunosuppression (see Tables 3A-B). These strategies can be overlapping (for example, cyclophosphamide is a chemotherapy killing cancer cells, but is also known to induce Treg suppression). Because OX40 signalling strongly extends the survival of antigen activated CD8+ and CD4+ T-cells (which is reasonably held to read on the result of immunomodulation as recited in instant claim 18 in light of the lack of a closed definition of the term ‘immunomodulation’ and the guidance that immunomodulatory molecules may be OX40L expressed on the surface of an exosome which enhance or inhibit an immune response (see paragraphs 0054-0055 of the instant specification)). Therapies that increase the antigenic load can synergize with agonistic anti-OX40. Therefore anti-OX40 can act as an adjuvant to an endogenic vaccination (surgery, radiotherapy, chemotherapy) or exogenic vaccination (see for example pg. 12/34 of Aspeslagh et al). Aspeslagh et al teach that one study successfully examined the effect of OX40L-Fc in combination with chemotherapy and vaccination in a glioma model. For example, for adoptive T-cell therapy, it was shown that anti-OX40 mAbs prolong life of the transferred T-cells. In addition, a suppressive action on Tregs (through Treg depletion or diminution of Treg suppression) by anti-OX40 could enhance the survival of CD4+ and CD8+ T effectors. Combining strategies to counteract all kind of immunosuppression with anti-OX40 mAbs resulted in dramatic synergistic effects against disseminated malignancies. In an established ovarian cancer model, combined anti-PD1/OX40 mAbs treatment markedly increase survival in that half of the mice were tumour free at 90 days. Similarly, combined intra-tumoural injections with a combination of a TLR9 agonist (CpG), anti-CTLA4 and anti-OX40 mAbs lead to tumour regression through Treg depletion even in cases of brain tumour deposits (see sections 6-8 and table 4).
While the teachings of Aspeslagh et al teach a fusion of co-administration, Aspeslagh et al do not teach the use of an exosome engineered to express OX40L on its surface and does not clearly teach transfection of an-exosome-producing cell as a means for producing exosomes which express a given molecule (such as OX40L) on their surface.
However, Johnsen et al teach that exosomes are endogenous nanocarriers mediating intercellular communication which are often characterized by cancer-associated changes. Their endogenous origin makes exosomes advantageous as drug carriers/vehicles for cancer treatment (see for example the abstract). Moreover, methods of engineering exosomes to express a given molecule appear to be well known in the art (see for example the graphical abstract showing the use of a vector to produce drug-loaded exosomes whereupon the drug appears to be surface-expressed on the exosome). In recent years, several studies have highlighted situations, in which an exosome-based drug delivery system has improved disease conditions, including studies performed on different cancer models (see section 4). Successful delivery of substantial amounts of therapeutic cargo from exosomes highly depends on an efficient method of their loading. Johnsen et al further teach that the most common means of loading therapeutic cargo into exosomes is by transfecting the exosome donor cell to overexpress a certain gene product that the cell will package into the exosome lumen or membrane for secretion and further cites studies demonstrating successful use of this method, including studies transfecting HEK293 cells (see for example table 2 and section 4.3.3). The use of a targeting peptide or protein is a requirement for targeted therapies, and thus must be present on the surfaces of exosomes for these to be relevant drug delivery vehicles, especially for applications in cancer treatment if chemotherapeutics with major adverse side effects are to be delivered. At the moment, a substantial amount of papers have been published with regard to using exosomes in drug delivery (see section 4.4 and Table 3).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Aspeslagh et al and Johnsen et al. The artisan would have been motivated to make and use the invention as claimed because Aspeslagh et al would have realized that the combination of OX40L and other known anti-cancer therapies such as an anti-PD-L1 antibody, anti-CTLA-4 antibody, and/or adoptive T cell therapy act synergistically to enhance treatment, enhance the immune response to cancer, and to evade/overcome primary and secondary resistance to any of the treatments as monotherapies. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Further regarding claim 70, Johnsen et al further teach a studies where the exosomes, in addition to containing large amounts of let-7a, also were endowed with a targeting peptide to facilitate efficient delivery after intravenous injection (see for example section 4.3.3 and note also that Table 4 teaches other methods of administration and dosing, including intravenous, oral, intratumoral, intraperitoneal, intraventricular, subcutaneous, and intranasal). Note that doses and dosage regimens are result effective variables. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989) (determination of suitable dosage amounts in diuretic compositions considered a matter of routine experimentation and therefore obvious). As both doses and dosage regimens were known to the ordinary artisan, it would have been obvious to optimize both the dosages and dosage regimens, including the particular dosing/dosing ranges and timing of dosing recited in the claims to treat cancer by administering known cancer agents through known means/methods/routes. It is not inventive to discover the optimum or workable ranges by routine experimentation, In re Aller, 220 F.2d 454, 456 (CCPA; see also In re Peterson, 315, F.3D, 1325 (Fed. Cir. 2003).
Only if the results of optimizing a variable are unexpectedly good can a patent be obtained for the claimed critical ranges, In re Geisler, 116 F.3d 1465, 1469, (Fed. Cir. 1997) quoiting in re Antoine, 559 F.2d 618, 620 (CCPA 1977)( Discovery for an optimum value or a result effective variable in a known process is ordinarily with the skill of the art. In re Boesch 617 F,2d 272, 276 (CCPA 1980)).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Aspeslagh et al and Johnsen et al. The artisan would have been motivated to make and use the invention as claimed because Aspeslagh et al and Johnsen et al teach that exosomes may be useful in treating cancer and Johnsen et al support that intravenous injection (as well as the modalities listed in table 4) is a known and predictable means of administration (said administration being required to bring about the therapeutic effects from the exosomes). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Further regarding claim 27, note that while Johnsen et al teach that there may be motivation to develop non-autologous exosomes, Johnsen et al teach that autologous exosomes are commonly what is used in the art (suggesting that use of autologous exosomes is most enabled in the art and more obvious to use with ease given the present state of the art-see for example section 6 of Johnsen et al as well as Johnsen et al in its entirety).
Claims 71-72 are rejected under 35 U.S.C. 103 as being unpatentable over Aspeslagh et al and Johnsen et al as applied to claims 17, 18, 22-24, 27, and 69-70, above, in further view of Frederick et al (US20180369374 A1; as cited in the Final Office Action dated 11/13/2024).
Aspeslagh et al and Johnsen et al teach the method of claim 17, but do not explicitly teach the use of an antimicrobial agent.
Regarding claims 71-72, Frederick et al teach mRNA combination therapy for cancer wherein, in some embodiments, a polynucleotide of any of the combination therapies disclosed herein, e.g., an mRNA encoding an immune response primer polypeptide, an mRNA encoding an immune response co-stimulatory signal polypeptide, an mRNA encoding a checkpoint inhibitor polypeptide, or a combination thereof, can be formulated in exosomes. The exosomes can be loaded with at least one polynucleotide and delivered to cells, tissues and/or organisms. Frederick also teaches pharmaceutical compositions suitable for administration to subjects (needed to effect the methods of treatment further disclosed in Frederick et al (see for example paragraph 2813).
Frederick et al further teach a formulation comprising an polynucleotide a carrier, an excipient, and a delivery agent (see for example, paragraph 0457), wherein the excipient may be a preservative (see for example, paragraph 0497), which may be an antimicrobial preservative such as benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal (see for example, paragraph 03477). Note further that Frederick et al teach that, in some embodiments, a polynucleotide of any of the combination therapies disclosed herein, e.g., an mRNA encoding an immune response primer polypeptide, an mRNA encoding an immune response co-stimulatory signal polypeptide, an mRNA encoding a checkpoint inhibitor polypeptide, or a combination thereof, can be formulated in exosomes (see paragraph 3457).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Aspeslagh et al and Johnsen et al. The artisan would have been motivated to make and use the invention as claimed because Frederick et al teach that this would work and be effective as an excipient in such a formulation for administration. Deciding upon which agent to use would be mere routine optimization of the formulation (see MPEP section 2144 (II)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Aspeslagh et al and Johnsen et al as applied to claims 17, 18, 22-24, 27, and 69-70, above, in further view of Kamerkar et al (Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017 Jun 22;546(7659):498-503; as cited in the Final Office Action dated 11/13/2024).
Regarding claim 67, as discussed above, Aspeslagh et al and Johnsen et al teach the method of instant claim 17.
The combined references do not explicitly teach that the exosomes expresses CD47 on their surface.
However, Kamerkar et al further teach that their results support that the presence of CD47 on exosomes allows for evasion from phagocytosis by the circulating monocytes and increases exosomes half-life in the circulation (see paragraph 2 of the discussion).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Aspeslagh et al and Johnsen et al. The artisan would have been motivated to make and use the invention as claimed in order to prolong/enhance the half-life/longevity of the exosomes as taught by Kamerkar et al. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses
A. Applicant argues that the references for not teach a reason to select for or end up with a population of exosomes wherein at least 50% of the exosomes express OX40L on their surface.
Response: As acknowledged by Applicant at pg. 6 of the 06/13/2025 remarks, Johnsen et al teach the desirability of increasing the yield and purity of the resulting exosome sample. One looking to produce OX40L-expressing exosomes would have reason to enhance the yield and purity of the exosome by selecting for the highest percentage of exosomes that express OX40L on the surface. Therefore, the Examiner believes that the motivation to select for at least a percentage of 50% of more (aka, the highest percentage of OX40L-expressing exosomes, in order to enhance sample purity) is clearly articulated in the rejection. Where Aspeslagh et al and Johnsen et al teach all of the active steps as broadly recited in the claims, the results, such as the resulting degree of OX40L-expressing exosomes, is presumed to be enabled and thereby made obvious. If this were not the case, it would appear that there is some step and/or product required to achieve this result which has not been included in the instant claims as drafted. Moreover, with Johnsen et al teaching that transfection of the exosome-producing cell is the most commonly/widely used means of loading exosomes with a variety of cargo (see for example section 4.3.3 and table 2 of Johnsen et al), the art is deemed to be predictably adapted for exosome loading and production of loaded exosomes. Applicant further cites to Johnsen et al’s teaching that the process of loading exosomes can be laborious and time consuming. These are secondary considerations bearing upon desirability of bringing said exosomes to market, but do not bear upon the predictability of producing said loaded exosomes and does not diminish the teachings of Aspeslagh et al and Johnsen et al that such loaded exosomes are predictably produced and employed for therapeutic purposes, by well-known means in the art. Secondary considerations do not deprive the art of its presumptive enablement and are not a teaching away so as to discredit adaptation/continued use of means known in the prior art.
Further, in light of the high level of generality at which the claim steps of stable transfection and exosomal collection/purification are recited (combined with Applicant’s implicit and explicit, respectively, admission that said steps are conducted through means known in the art (see for example paragraphs 0035 and 000135), where the art known methods would appear to fall within the scope of what is claimed, as presently drafted and do not appear discernibly different. Therefore, the transfection efficiency is presumed to be equivalent. Note that the recitation that at least 50% of the collected/purified exosomes express OX40L is not drafted to reflect of require an active step, but is drafted to reflect a result of practicing the method encompassed by claim 17. Therefore, the recited result of at least 50% OX40L expressing exosomes is presently considered an inherent feature of the claim as drafted, which only requires the general active steps of stable transfection, collection and purification of exosomes, and administration of said exosomes for treatment. Because the method resulting from the combined prior art references meets the generic limitations of the claims, as presently drafted, this result is presumed inherent, absent evidence to the contrary, upon which the claims would likely be revealed to suffer from deficiencies with respect to 35 USC §112(a).
As presently articulated, this argument is unpersuasive at this time and the rejections of record, as they appear in this office action, are maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ovadya et al (US20180117173 A1; as cited in the Final Office Action dated 11/13/2024) teach that recombinantly engineered antigen-presenting cells such as dendritic cells, for example, may be modified by recombinant technology to express increased levels of antigen presenting machinery, adhesion and/or co-stimulatory molecules, including MHC class I/antigen complexes, MHC class II/antigen complexes, CD1, hsp70-90, CD9, CD63, CD81, CD1 1b, CD1 1c, CD40, CD54 (ICAM-1), CD63, CD80, CD86, 41BBL, OX40L, chemokine receptor CCR1-10 and CXCR1-6, mannose-rich C-type lectin receptor DEC205 and Toll-like receptors TLR4 and TLR9 or membrane-bound TGF-β. The exosomes derived from these recombinantly engineered antigen presenting cells will express these additional molecules and can transfer them to the T helper cells, T regulatory cells, or dendritic cells upon absorption (see paragraph 0350). These cells and their exosomes can be administered to a subject in order to target senescent cells for treating and diagnosing diseases. Cellular senescence, a stable form of cell cycle arrest, is a mechanism limiting the proliferative potential of cells. Senescence can be triggered in many cell types in response to diverse forms of cellular stress. It is a potent barrier to tumorigenesis and contributes to the cytotoxicity of certain anti-cancer agents. While senescence limits tumorigenesis and tissue damage in a cell autonomous manner, senescent cells induce inflammation, tissue ageing, tissue destruction and promote tumorigenesis and metastasis in a cell non-autonomous manner in the sites of their presence. Therefore, their elimination might lead to tumor prevention and inhibition of tissue ageing. Indeed, elimination of senescent cells was shown to slow down tissue ageing in an animal model (Baker et al., 2011) (see paragraphs 0001, 0002, and 0006).
Codiak Biosciences (WO2019133934A2; as cited in the Final Office Action dated 11/13/2024) teach exosomes (extracellular vesicles) for immune-oncology/anti-inflammatory therapy for treating cancer (see title and abstract and claim 1) having OX40L (see claims 1, 4, 7-8, and 11) and which may have surface CD47 (see paragraph 00148), which may deliver a protein payload (intravesicular payload) (see paragraph 00151) and which may comprise a second immunomodulating component which may be an antibody, such as an inhibitor of CTLA4 (see claims 40 and 67 and paragraph 0023), for intravenous administration (see paragraph 0044).
Meyer et al (Pseudotyping exosomes for enhanced protein delivery in mammalian cells. Int J Nanomedicine. 2017 Apr 18;12:3153-3170. doi: 10.2147/IJN.S133430) fused a set of fluorescent and luminescent reporters with vesicular stomatitis virus glycoprotein (VSVG) and showed successful targeting and incorporation of VSVG fusions into exosomes by gene transfection and fluorescence tracking. Meyer et al subsequently validated this system by live cell imaging of VSVG and its participation in endosomes/exosomes that are ultimately released from transfected HEK293 cells. Full-length VSVG (fVSVG) gene-encoding single-transmembrane protein was used for making various fusion constructs. HEK293 cells grown on 15 cm plates (70%–80% confluence) were transfected with FuGene transfection reagent. Meyer et al cotransfected HEK293 cells with fVSVG-RFP (red) and CD63-GFP (green), a validated marker of exosomes. High-resolution fluorescence imaging of cells transfected with these two constructs also revealed extensive overlap of the green and red fluorescence signals. Meyer et al explain that these results confirm the expectation that fVSVG participates in the biogenesis of the endocytic compartment as presecreted exosomes. Together, the results of these imaging studies are consistent with our hypothesis that fVSVG serves as a molecular scaffold that both integrates and correctly projects appended proteins, including RFP, in the exosomal membrane. The readily detectable fluorescence of RFP suggests that protein payloads on fVSVG are functional, and protein integration into the exosome membrane is highly efficient.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678