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 .
Applicant should note that the instant application has been reassigned to a new examiner and to Art Unit 1617.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/26/2026 has been entered.
Status of the Claims
Pursuant to the amendment dated 05/26/2026 new claims 11-20 have been added. Claims 4, 7, and 8 were cancelled previously.
Claims 1-3, 5, 6, and 9-20 are pending and under current examination.
All rejections not reiterated have been withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5, 6, and 9-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
The specification, while being enabling for increasing expression of CD54, CXCL1, CCL3, CCL5, and TNF-a in isolated bone marrow derived macrophages (BMDM) ex vivo, does not reasonably provide enablement for the full scope of enhancing immunity by administering a therapeutically effective amount of exosomes isolated from cow milk or goat milk resulting in increased expression of CD54, CXCL1, CCL3, CCL5, and TNF-a in any macrophage in any tissue. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)).
These include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based
on the content of the disclosure
All of the Wands factors have been considered with regard to the instant claims,
as discussed below:
(A) The breadth of the claims/(B) The nature of the invention:
The claims are directed to a therapeutic method of enhancing immunity of a subject comprising administering a therapeutically effective amount of exosomes isolated from cows milk or goat milk to the subject wherein the therapeutically effective amount of exosomes is effective to increase expression of CD54, CXCL1, CCL3, CCL5, and TNF-a in macrophages of the subject, wherein the exosomes are not drug carriers, and wherein the exosomes are positive for CD9, CD63, CD81, and TSG101. the term enhancing embraces subjective improvements e.g. to increase or improve in value, quality, desirability, or attractiveness.
Thus, the claims require the exosomes to (1) enhance immunity (see definition of “enhancing” above for scope), (2) have a therapeutic effect upon administration, and (3) to result in a specific cytokine profile in macrophages of the subject to whom the exosomes were administered. Claims 1-3, 5, 6, and 9 do not specify the condition for which the exosomes are therapeutic. Claims 11-15 indicate the method must have the effect of enhancing immunity to treat or reduce the risks of infection in a subject in need thereof, and claims 16-20 require enhanced immunity of a cancer patient. Remaining claims further narrow the source of the exosomes or limit the exosomes in terms of the methods used to produce them.
As such, the scope of the claims is immense.
(C) The state of the prior art/(D) The level of one of ordinary skill/(E) The level of predictability in the art:
The artisan of ordinary skill would be an individual or team with advanced degree(s) in biomedical sciences, therefore the level of skill is high.
The immune system is defined in the instant specification as “a self-defense response that distinguishes exogenous and endogenous foreign matter in the body, and eliminates and metabolizes them”. The immune system, i.e. the organ systems, cells, and molecular mediators that achieve the claimed immunity, is incredibly complex network and the conditions under which “enhancement” might occur are highly unpredictable and context dependent. As stated above, in order to practice the full scope of the claimed invention, one having ordinary skill would need to predict which of all the pathologies that afflict animals would respond to administration by any route of exosomes derived from cow or goat milk by enhancing immunity and increasing expression of CD54, CXCL1, CCL3, CCL5, and TNF-a in macrophages, in such a way as to provide therapeutic benefit.
Regarding the predictability of biological systems to respond with an enhancement of immunity: Soliman et al. (eds; Frontiers in Immunology, website; 2026) describe inflammation, an element of innate immunity, as “highly dynamic and context-dependent, shaped by the nature of the inflammatory stimulus, the tissue microenvironment, host metabolic status, microbial interactions, and disease stage. Rather than a uniform cascade, inflammation is now recognized as a spatially and temporally tailored process, with distinct molecular and cellular programs governing its initiation, propagation, resolution or chronicity. This nuanced view of inflammation is transforming our understanding of immune regulation in both health and disease.” Soliman describes “tissue-specific immune cells exhibit diverse transcriptional and metabolic profiles that influence their inflammatory responses. Non-immune cells such as epithelial, stromal, and endothelial cells also contribute actively to shaping these local immune environments. Moreover, extrinsic factors, such as circadian rhythms, dietary signals, and microbiota-derived metabolites, modulate inflammatory tone and resolution capacity in a context-dependent manner.” Soliman states “The failure to resolve inflammation is a driving force behind many chronic diseases, including autoimmunity, fibrosis, cardiovascular disease, neuroinflammation, and cancer. Despite major therapeutic advances, many interventions still target generalized inflammatory mechanisms rather than addressing the specific context in which inflammation occurs.” Clearly the innate immune system alone is enormously complicated and response to a given stimulus is contingent upon many factors such as which tissue is exposed, when, and any underlying pathologies. One having ordinary skill would not have been able to predict a priori the components of the innate immune system that would be enhanced in such a way to provide a therapeutic effect in the context of every possible disease or condition influenced by immunity/inflammation. Although a great deal has been learned about immune system functioning, more remains to discover regarding the factors influencing its activity and the context under which an active immune system is harmful vs. therapeutic.
Regarding upregulation of CD54, CXCL1, CCL3, CCL5 and TNF-a in macrophages in a manner that has therapeutic effect, Benmoussa (of record) reports that milk extracellular vesicles are generally potent at preventing inflammation in mouse models of rheumatoid arthritis and show beneficial effects in cancer; however, they may increase inflammation in some contexts, citing Nordgren et al (of record). Nordgren teaches that administration of milk exosomes result in a shift of lung macrophages towards an M1 polarization, having increased TNF and generally worsening pathological lung inflammation, i.e. the effect was not therapeutic, despite enhancing immune system activity and increasing the expression of at least one of the cytokines required to be increased in the instantly claimed method, TNFa. Benmoussa also reports that in the colon, expression of proinflammatory cytokine such as TNFa decreases when milk extracellular vesicles containing exosomes are administered in food (P100K EVs contain exosomes: page 1; P100K EVs cause most of the cytokines/chemokines to decrease, including TNFa). (The examiner notes that a different cytokine expression profile could be observed in other organ systems such as in the bone marrow derived macrophages described in the instant specification because, as discussed herein, immune response is highly context dependent including which organ system is involved.) Thus, the effect of exosomes on macrophage cytokine expression was unpredictable, and the extent to which the cytokine expression would be therapeutic was also unpredictable.
Regarding the requirement for the administration of cow or goat milk exosomes to have a therapeutic effect, enhanced immunity can be beneficial, or can further drive pathologies. The pro- and anti-carcinogenic effects of macrophages in cancer is taken as exemplary. The immune system is one of the body’s first defenses against cancer; however, its activity is also required for cancer development and progression. Cancer-associated inflammation, which is present at different stages of tumorigenesis, contributes to genomic instability, epigenetic modification, induction of cancer cell proliferation, enhancement of cancer anti-apoptotic pathways, stimulation of angiogenesis, and cancer dissemination (Gonzalez Genes & Development 32:1267-1284; 2018; page 1267, right col). Gonzalez provides several pictorial summaries of the beneficial and harmful effects of the immune system on cancer:
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Gonzalez explains (pages 1269-1270): Macrophages sense and respond to infections and tissue damage and are essential for tissue homeostasis and repair; however, they are also drivers of chronic inflammation and have been described in every stage of cancer progression. High grade tumor associated macrophages are associated with poor prognosis. Macrophages can adopt an M1 proinflammatory phenotype or M2 anti-inflammatory phenotype, and anti-tumor macrophages display an M1-like polarization that helps with elimination of tumor cells. Over the course of tumor development, macrophages shift towards an M2-like polarization that promotes tumor progression in various ways. Although tumor-associated macrophages mostly promote tumor progression, they can sometimes exert anti-tumoral roles. Tumor-associated macrophages are recruited to the tumor be various chemokines, including CCL5, whose increase is required by the instant method. Finally, Gonzalez points out that although the M1-like/M2-like paradigm has been useful, it is more likely that a spectrum of differentiated tumor-associated and metastasis-associated macrophages exist and that the M1-like/M2-like is oversimplified.
Regarding potentially therapeutic effects of TNFa upregulation in macrophages after cow or goat milk exosome administration, Ben-Baruch (Frontiers in Immunology; 13, May 2022) explains the following: TNFa has the potential to shrink tumors upon local administration in clinical trials; however, complete remission was never observed, and systemic administration resulted in multiple side effects and low efficacy. Higher endogenous TNFa expression is associated with advanced disease, TNFa is pro-inflammatory and its expression by inter alia leukocytes (a category that includes macrophages) to inflammatory cell recruitment and pro-metastatic effects. TNFa can act directly on cancer cells to promote metastasis, generate cancer stem cells, and promote epithelial to mesenchymal transition (associated with malignancy), invasiveness, resistance to therapy, and metabolic changes (page 1). TNFa has been identified as a powerful pro-cancer cytokine in many malignancies, suggesting that its inhibition would be therapeutic, rather than increasing its expression. One can begin to understand the dichotomous roles of TNFa on cancer development and progression by recognizing that the TNFa/TNFaR network includes many different members, generating intricate interactions that are spatially and temporally regulating leading to diverse consequences under different conditions. When the TNFa/TNFaR network is considered in cancer therapy, the “target” approach may apply better than the “therapy” tactic (i.e. it may be better to reduce the effects of TNFa, than to attempt to activate TNFa signaling). However, to date, very few clinical studies have analyzed the therapeutic value of inhibiting TNFa signaling (page 2). Accordingly, even within the narrower scope of “enhancing immunity of a cancer patient” delimited in instant claim 16, it would have been impossible for one having ordinary skill to a priori predict the circumstances under which upregulated TNFa in macrophages would have a therapeutic effect.
Clearly it would have been impossible for one having ordinary skill to practice the full scope of the claimed invention because the would have to predict the circumstances under which administering exosomes would (1) cause macrophages to increase expression of CD54, CXCL1, CCL3, CCL5, and TNF-a and also (2) have a therapeutic effect. The level of unpredictability in the art as of the instant effective filing date was exceptionally high.
(F) The amount of direction provided by the inventor/(G) The existence of working examples:
The specification provides a high level description of immune function, defining immunity as a self-defense response that distinguishes exogenous and endogenous foreign matter in the body, and eliminates and metabolizes them. A several sentence overview of innate and acquired immunity is followed by a short list of a handful of the cells and molecules that mediate the immune system’s response.
In example 11, the specification describes upregulation of CD54, CXCL1, CCL3, CCL5, and TNF-a expression in bone marrow derived macrophages (BMDM; of unidentified organism) that were grown in culture and then treated with commercial milk-derived exosomes and colostrum exosomes.
Thus, the amount of direction provided by the inventor and existence of working examples represent only a very small scope of the claimed breadth.
(H) The quantity of experimentation needed to make or use the invention based
on the content of the disclosure:
In view of the foregoing analysis, the quantity of experimentation required to practice the full scope of the invention, as claimed to enhance immunity such that a therapeutic effect is achieved, is undue.
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.
Claims 1-3, 5, 6, and 9-20 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.
The term “enhancing” in claims 1, 11, and 16 is a relative term which renders the claim indefinite. The term “enhancing” means to heighten or increase, especially to increase or improve in value, quality, desirability, or attractiveness. The term “enhancing” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As such, the requisite effect of the exosomes on immunity is wholly unclear and one having ordinary skill in the art cannot unambiguously ascertain the metes and bounds of the claimed invention.
Claims depending from rejected claims have also been rejected because they incorporate all of the limitations of the claims from which they depend, but fail to resolve the indefiniteness concerns outlined above.
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 1-3, 5, 6, and 9-20 are rejected under 35 U.S.C. 103 as being unpatentable over Benmoussa et al. Scientific Reports|NatureResearch 9:14661; publication date: 10/10/2019; of record) in view of Ayala-Marr et al., (Recent advances and challenges in the recovery and purification of cellular exosomes, August 30, 2019; of record) as evidenced by Soliman et al. (eds; Contextual Inflammation: mechanisms of Immune Adaptation Across Tissues, time, and Disease States, Frontiers in Immunology, website; 2026) and as evidenced by Anchordoquy et al. (US 20210369860).
With regard to claims 1, 11, and 16, Benmoussa discloses that extracellular vesicles (EVs; P35K and P100K, designating the pellets from 35,000g and 100,000g centrifugation, respectively) from cow’s milk improve colitis outcome in a mouse model. The P100K fraction represents exosomes (page 1: “the most studied of which are exosomes. These small vesicles of ~100nm in diameter are released when multivesicular bodies (MVB) fuse with the cell membrane and pellet at centrifugation speeds of 100,000g”). Benmoussa also discloses another fraction of EVs having comparable size and shape that sediment at 35,000g (i.e. P35K EVs; page 1). Benmoussa evaluates the effect of these two EV fractions on symptoms and inflammation in a mouse model of colitis (title, pages 11-12). Mice were fed twice daily with these isolated EV preparations (isolated exosomes) or control (page 12; i.e. the exosomes were administered orally, which the examiner considers to fall within the scope of “functional food”). Benmoussa found that EVs might modulate inflammation and immune cell infiltration preventing degradation of the colon and restore normal mucin secretion after colitis (page 4: Milk EVs restore normal colon histologic architecture and extracellular matrix secretion). Benmoussa also observed the following (page 6 Milk EVs modulate inflammation in DDS-induced colitis): colitic mice had higher levels of inflammatory cytokines and feeding colitic mice P35K EVs (extracellular vesicles that are not considered identical to exosomes) increased expression of chemokines and immune cell proliferation-differentiation-survival modulators including CXCL1, CCL5, and TNF-a. P100K EVs (traditional method of isolating exosomes, see Benmoussa, page 1) resulted in a different profile of cytokine expression, most were lowered or restored to levels comparable to or lower than healthy controls. The instant claims require “enhancing immunity” such that a therapeutic effect is achieved. As noted above, the term enhancing embraces subjective improvements e.g. to increase or improve in value, quality, desirability, or attractiveness. In the case of Benmoussa’s studies, administration of the EVs, which include exosomes, results in a shift in expression of cytokines that contribute to the pathology of colitis, such that the colitic colon is restored to a healthy state. Therefore, the examiner considers the method to result in enhanced immunity with therapeutic results.
Instant claims 1, 11, and 20 also recite the intended outcomes of increased expression of CD54, CXCL1, CCL3, CCL5, and TNF-a and instant claims 10, 15, and 20 require the method to activate T cells and dendritic cells in the subject. Benmoussa observed elevated CXCL1, CCL5, and TNF-a after administration of the P35K EVs, and upon administration of the P100K fraction that contains exosomes Benmoussa observed decreased pro-inflammatory cytokines, including a decrease in TNF-a in the colon. However, the immune system’s response to a stimulus is highly dependent upon context (Soliman, entire document), bovine exosomes are systemically absorbed through the gastrointestinal tract (Anchordoquy: 0121), and the instant claims and specification indicate that administration of isolated bovine exosomes has the effect of increasing CD54, CXCL1, CCL3, CCL5, and TNF-a in bone marrow derived macrophages (BMDM). In view of the foregoing, the preponderance of evidence supports the conclusion that the BMDMs in Benmoussa’s method would also have responded by increasing expression of CD54, CXCL1, CCL3, CCL5, and TNF-a in bone marrow macrophages and would exhibit the requisite effect on T-cells and dendritic cells upon oral administration because the administered exosomes are the same. The examiner considers the requisite outcome of the instant claims to necessarily have been present in Benmoussa’s invention, absent evidence to the contrary. Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of the claimed product. See In re Ludtke, 441 F.2d 660, 169 USPQ 563 (CCPA 1971). Whether the rejection is based on "inherency" under 35 USC 102, on "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
As noted above, Benmoussa teaches that P100K fraction of milk EVs contain exosomes and discloses an additional subset of EVs that sediment at 35,000g have immunomodulatory properties (page 1; page 6), but does not disclose wherein the exosomes are positive for CD9, CD63, CD81, and TSG101.
Ayala-Marr teaches that breast milk-derived exosomes are used in regulation of immune responses and are typically isolated through differential centrifugation (Table 1, page 3039). However, immunoaffinity techniques can also be used to selectively isolate exosomes from complex biological fluids. Immunoaffinity approaches take advantage of the many proteins, receptors, lipids, and polysaccharides that are present in the outer surface of exosomes. Exosome biomarkers such as CD63, CD81, CD9, and TSG-101 have been used in immunoaffinity techniques to selectively identify and isolate specific subpopulations of these types of exosomes. Immunoaffinity techniques are usually coupled to other strategies that integrate the specific selection of exosomes with a physical separation or isolation procedure. Such strategies allow the enrichment of the sample with exosomes or the depletion of unwanted vesicles (2.4 Immunoaffinity procedures, page 3043). The main advantage of the immunoaffinity procedures used with this purpose is the better quality and purity of the resulting isolated exosomes. Since antigen-antibody interactions are highly specific, this technique is very useful to selectively isolate a subpopulation of extracellular vesicles without contaminants (page 3044, third paragraph).
As Benmoussa discloses exosomes, and CD63, CD81, CD9, and TSG-101 are markers of exosomes, the preponderance of the evidence supports the conclusion that as CD63, CD81, CD9, and TSG-101 are present on the P100K fraction of EVs (i.e. the exosomes, as evidenced by Ayala-Marr, above), although this is not discussed in Benmoussa. Recognizing that the Office cannot know for certain that these markers are present on the exosome fraction reported by Benmoussa, in the alternative, it would have been prima facie obvious to have differentially isolated exosomes comprising the additional biomarkers (i.e., are positive for) CD63, CD81, CD9, and TSG-101 since these biomarkers are used in techniques that selectively isolate a subpopulation of extracellular vesicles without contaminants resulting in better quality and purity of the resulting isolated exosomes, as taught by Ayala-Marr.
With regard to the preamble of instant claim 11, requiring treating or reducing risk of infection, the examiner notes that the phrase “reducing risk of infection” is an intended outcome. All of the active method steps are taught by Menmoussa/Ayala-Marr, therefore the examiner considers the method of Benmoussa to inherently result in reduced risk of infection.
With regard to the preamble of claim 16, Benmoussa proposes that the EVs, including exosomes, would be useful in countering inflammation in cancer, therefore it would have been prima facie obvious to administer the EVs to cancer patients.
With regard to claims 2, 12, and 17, as discussed above, the milk is from cows.
With regard to claims 3, 5, 6, 13, and 18, Benmoussa/Ayala-Marr teach a bovine milk-derived exosome used for enhancing immunity of a subject. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process, In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), see MPEP 2113. The final product disclosed in the instant application holds no patentably distinct structural differences from the final product disclosed by Benmoussa/Ayala-Marr.
With regard to claims 9, 14, and 19, as noted above the mice are fed the milk EVs, which the examiner considers to teach formulating as a functional food.
Claims 3, 5, 6, 13, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Benmoussa et al. Scientific Reports|NatureResearch 9:14661; publication date: 10/10/2019) in view of Ayala-Marr et al., (Recent advances and challenges in the recovery and purification of cellular exosomes, August 30, 2019; of record) as evidenced by Soliman et al. (eds; Contextual Inflammation: mechanisms of Immune Adaptation Across Tissues, time, and Disease States, Frontiers in Immunology, website; 2026) and as evidenced by Anchordoquy et al. (US 20210369860) as applied to claims 1-3, 5, 6, and 9-20 above, and further in view of Izumi et al., (EP 3192518 A1, July 19, 2017; Morinaga Milk Industry, cited by applicant on IDS), Bolen et al. (US 2018/0193270 A1, July 12, 2018; of record) and Thery et al. (Journal of Extracellular Vesicles, 2018; of record).
Instant claims 3, 5, 6, 13, and 18 have been rejected as being obvious over Benmoussa and Ayala-Marr as set forth supra. However, purely arguendo, for the purposes of complete prosecution, and for the purposes of this ground of rejection only, the product by process language of instant claims 3, 5, 6, 13, and 18 is also obvious as follows:
Izumi discloses a method for isolating exosomes from milk, comprising: a centrifugation step of centrifuging raw milk so as to remove fat and cells at 4 degrees Celsius; a step of removing centrifuged fat and cells; a step of adjusting the pH to 4.6 by adding 10% acetic acid and precipitating casein; a step of centrifuging the milk in which casein is precipitated at 4,500 × g and 4°C for 30 minutes, and collecting a supernatant; and a step of filtering the collected supernatant by using a 0.22 µm filter ([0046]), reading on claims 3-4 and 6-7.
Bolen teaches methods of producing exosomes (Abstract) from milk ([0009]) by a first step of centrifugation ([0970] – [0972]), then a first filtration step to further remove fat and cells therefrom ([0973 – 0979]), then a dilution step of adding distilled water to the filtered milk as needed (approximately 10 mL) in order to satisfy manufacturer instructions for properly filled/balanced tubes ([0980]), reading on claim 3.
Thery teaches that for the separation of extracellular vesicles (i.e. exosomes), there is no single optimal separation method, so choose based on the downstream applications and scientific question (Table 1, page 13). Thery et al. teaches the k factor can be determined from the rotor type, tube/adapter, and centrifuge speed and must sometimes be adjusted (Table 1, subparagraph a). Thery et al. teaches for filtration techniques; one must take care to remove cells and other large membranous structures prior to ultrafiltration and that the pore size of the matrix should be taken into account (Table 1 subparagraph b). Thery et al., teaches that time and temperature are also factors that may require adjustment during the exosome separation process (Table 1, Examples for classical technique). A person of ordinary skill in the art, with a reasonable expectation of success, would have been able to adjust the k factor and time of the first centrifugation step to encompass 4,000 to 6,000 x g for 20 to 40 minutes as recited in claim 4, the desired mesh size of the strainer to 20 to 60 µm or 30 to 50 µm as recited in claims 3 and 5, an equal amount of distilled water added to the filtered milk or goat milk as recited in claim 3, and the temperature to room temperature as recited in claim 7 in the instant application with repeated experimentation and a reasonable expectation of success based on the teachings of Thery.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the exosome preparation processes of Izumi and Bolen to prepare the exosomes taught by Benmoussa/Ayala-Marr motivated by the desire to optimize the separation process according to the downstream application of the exosomes (Thery, Table 1) and to adjust the volume of liquid in the tubes in order to satisfy manufacturer instructions for properly filled/balanced tubes (Bolen, ([0980]).
Response to Arguments
Applicant’s arguments, see pages 7-10, filed 05/25/2026, with respect to the rejection of the claims under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made as set forth above. Applicant’s arguments have been fully considered but are moot as they do not apply to the reasoning underlying the current rejection.
In a previous response filed 07/15/2025, Applicant pointed out that Benmoussa’s P35K EV fraction does not contain exosomes. The examiner agrees with Applicant’s interpretation of Benmoussa’s disclosure. In addition to administering the P35K fraction, Benmoussa teaches therapeutic benefit for an inflammatory disease administering the P100K fraction that does contain exosomes, and proposes extending this to other conditions driven by pathological inflammation. See the rejection above for further details regarding the examiner’s obviousness conclusion.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5, 6, and 10-13, 15-18, and 20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 14 and 21, 23, 24, 26, 28, 30, 31, 33, 35, 37, and 38 of co-pending Application No. 17/780391;
claims 1 and 3-9 of co-pending Application No. 18/133,918; and
claims 1-9 of co-pending Application No. 18/133,901
in view of Benmoussa et al. Scientific Reports|Nature Research 9:14661; publication date: 10/10/2019).
The co-pending applications claims teach a method comprising administering a therapeutically effective amount of exosomes isolated from colostrum to the skin of the subject (see e.g. page 13 of the ‘886 application for the scope of the term “administering”); and the ‘901 applicant embraces application to the skin of the scalp in the form of a shampoo. The claims do not expressly recite a limitation regarding enhancing immunity.
Benmoussa teaches that bovine milk-derived extracellular vesicles (EVs), including exosomes, modulate the immune system in a manner that is therapeutic for inflammation of the colon and for cancer.
It would have been prima facie obvious for one of ordinary skill to administer the exosomes claimed in the copending applications in a patient to enhance their immunity. The artisan of ordinary skill would have been motivated to do so in order to treat the patient and had reasonable expectation of success because Benmoussa shows restoration of colon health in a mouse model of colitis.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments, see pages 7-10, filed 05/25/2026, with respect to the rejection of the claims under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made as set forth above. Applicant’s arguments have been fully considered but are moot as they do not apply to the reasoning underlying the current rejection.
Conclusion
No claims are allowed.
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/KATHERINE PEEBLES/ Primary Examiner, Art Unit 1617
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