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's amendments to the claims filed on 08-06-2024 have been received and entered. Claims 3-6, 8, 10, 13, 17, 20, 22-23, 25, 29, 35-37, 40 have been amended. Claims 7, 9, 11-12, 14-16, 18-19, 21, 24, 27-28, 30-34, 38-39, 41-55 have been canceled. Claims 1-6, 8, 10, 13, 17, 20, 22-23, 25-26, 29, 35-37, 40 are pending and under consideration in the instant application.
Priority
This application claims priority from US provisional application no 63/500,786 filed on 05/08/2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10-01-2024 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Objections
Claims 5, 6 and 23 are objected to because of the following informalities:
Claim 5 appears to recite the repetition of ‘at least’ in the phrase “at least at least 10 times”. Additionally, Claim 5 appears to have the lack of the conjunction “or” between the phrases “at least 40 times” and “at least 50 times”. These grammatical issues make the claim somewhat confusing.
Claim 6 appears to label the steps (a)-(g); however, there is no step (c) between step (b) and (d).
Claim 23 appears to label the steps (a)-(d); however, there is no step (c) between step (b) and (d).
Appropriate correction is required.
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 1-6, 8, 10, 13, 17, 20, 22-23, 25-26, 29, 35-37, 40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the phrase “treating an ovarian disorder or condition”. However, the scope of the term “ovarian condition” encompasses any condition including normal or known or unknown disease conditions. Likewise, the scope of the term “ovarian disorder” is also extremely broad. The instant specification does not provide definitions or guidance for the term terms “disorder” or “condition” in any limiting way. In addition, the two terms are presented as alternatives in the preamble of the claim. It is unclear in this context whether, and to what degree, the two terms overlap in scope. Therefore, the metes and bounds of the limitation “ovarian disorder or condition” could not be ascertained.
Claims 2-6, 8, 10, 13, 17, 20, 22-23, 25-26, 29, 35-37, 40 directly or indirectly depends from the rejected base claim. Appropriate correction and/or clarification is required.
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 1-6, 8, 10, 13, 17, 20, 22-23, 25-26, 29, 35-37, 40 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.
Claims are directed to a method of treating an ovarian disorder or condition, the method comprising administering an effective amount of a permeate media composition to a subject in need thereof, wherein the permeate media composition comprises at least one exosome and at least one component isolated from an extracellular matrix.
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus. 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. Diamond 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. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304,312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43). USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
The claims encompass a genus of treating any ovarian disorder or condition, the method comprising administering via any administration routes an effective amount of a permeate media composition to a subject in need thereof, wherein the permeate media composition comprises any amount of exosome derived from any tissue/method of isolation and any amount of component isolated from an extracellular matrix derived from any tissue/method of isolation (As discussed below, it is known in the art that exosomes from different sources or prepared using different methods vary in the types and concentrations of active molecules, which may further increase the risk of affecting non-target tissues see Liu et al below).
For example, the claims are broadly directed to a method of treating any ovarian disorder or condition, according to claim 40, the ovarian disorder or condition comprises any of polyovarian insufficiency (POI), polycystic ovary syndrome (PCOS), vaginal atrophy, ovarian cysts, premature ovarian failure, ovarian torsion, ovarian cancer, endometriosis, uterine fibroids, gynecologic cancer, interstitial cystitis, sexually transmitted diseases, cervical cancer, uterine cancer, pelvic inflammatory disease, or prolapsed uterus. The method comprising administering via any administration routes such as dermal (topical & transdermal), anal/rectal, oral, sublingual & buccal, inhalation, otic & ocular, vaginal , nasal administration routes etc.an effective amount of a permeate media composition to a subject in need thereof, wherein the permeate media composition any amount of exosome derived from any tissue/method of isolation and any amount of component isolated from an extracellular matrix derived from any tissue/method of isolation (As discussed below, it is known in the art that exosomes from different sources or prepared using different methods vary in the types and concentrations of active molecules, which may further increase the risk of affecting non-target tissues see Liu et al below).
It is also noted that the claims broadly encompass treating any ovarian disorder or condition. However, the instant disclosure only provides examples for polyovarian insufficiency (see examples 1-5 of the instant disclosure) and does not exemplify method and/or mechanism that could be used to treat any ovarian disorder as listed above.
The working examples and guidance provided: The specification discloses:
Example 1: preparation of exosome and MSC compositions: An umbilical cord was obtained, dissected into tissue samples, washed and stored in PBS in a petri dish. After MSCs were isolated in a single cell stack, a standard MSC cell expansion media and MSC expansion techniques were used to expand the cells from a single layer cell stack to 10-layer cell stack to 15-liter bio reactor. Mesenchymal stem cells were collected in the retentate, and the extracellular matrixes components and exosomes were collected in the permeate (see the disclosure [0190]- [0194]).
Example 2: the exosome composition in Example 1 was analyzed and compared to a commercially available exosome preparation (e.g., AMNIOSOME). Both compositions were analyzed by conventional proteomic techniques. It was found that levels of over 1900 compounds/growth factors/or other components found in extracellular matrix were elevated in the composition of Example 1 compared to levels in the commercially available preparation (see the disclosure [0195]).
Example 3: treatment of polyovarian insufficiency with mesenchymal stem cell composition: A preliminary clinical trial was conducted with patient's autologous BM hMSCs (clinicaltrials.gov, ID: NCT02696889). In this trial, 5 patients were successfully treated, 3 at the University of Chicago, IL, and 2 at Augusta University, Augusta, GA. First patient estrogen level was <10.9 pg/ml prior to MSC implantation and after I-week post MSCs implantation, increased three times to 20 pg/ml. At six months post MSC injection, estrogen levels reached 26.1 pg/ml. Other patients exhibited similar response to the MSC treatment (see the disclosure [0196]).
Example 4 - treatment of polyovarian insufficiency with exosome composition: A double-blind placeho-controlled study will be performed to test the efficacy or an exemplary exosome composition on treating Polyovarian Insufficiency in patients. study participants will need to be diagnosed with POI (polyovarian insufficiency). Due to the chronic nature of the condition. diagnosis and screening reports must be from the past 12 months. The EV-Pure products ("Exosome compositions") will be prepared as described in Examples 1 and 2 and supplied to the clinical site frozen on dry ice in vials corresponding lo individual doses (each vial containing 15x I0'l, 30x I0q, or 60x 109 cxosomes in a I mL volume). At time of administration, a vial will be thawed at room temperature for no less than 20 minutes immediately prior to the administration to the study participants. An 18-gaugc needle attached to a 5 mL syringe will be used to aspirate out the contents of the vials (l mL volume) and mixed with 50 mL of 0.9% saline for infusion using sterile techniques (see the disclosure [0197]- [0205]).
Example 5 - treatment of polyovarian insufficiency with exosome composition - Multiple Dose Treatment: in Table 4, patients will be administered one, two or three doses of the EV-Pure composition (at either 15, 30 or 60 x 109 exosomes per dose) and will also optionally be treated with one two or three doses or the MSC composition (with 10, 30, or 250 x 107 MSC cells per dose). Doses will be administered weekly or monthly. After treatment, patients will be evaluated using methods and based on standards described above (see the disclosure [0206]- [0207]).
None of the working examples teaches treating any ovarian disorder or condition other than polyovarian insufficiency. The instant specification does not provide guidance for how permeate media composition comprises at least one exosome and at least one component isolated from an extracellular matrix can be applied to treat various type of ovarian disorder or condition as encompassed by the claims.
The claims are broadly directed to treating an ovarian disorder or condition. However, the effectiveness and criteria of treating an ovarian disorder or condition was unpredictable before the effective filing date of the claimed invention.
1. The use of any amount of exosomes derived from any tissue carrying any cargo for treating ovarian cancer is unpredictable before the effective filing date of the claimed invention. Chen et al (Journal of Pharmaceutical Analysis 15 (2025) 101170, Doi: 10.1016/j.jpha.2024.101170) teach “Despite the growing interest in exosome research, several unresolved questions remain. Most exosome-based treatments are still in the experimental phase and lack extensive clinical trials. One major challenge is the isolation of exosomes, which involves addressing issues related to standardization of isolation methods, exosome heterogeneity, potential toxicity of therapeutic exosomes, and detailed investigation into their molecular components. The complexity of exosome heterogeneity stems from factors such as size, molecular diversity, and varying cellular origins. In ovarian cancer patients, circulating exosomes are a mixture of vesicles released from different regions of the female reproductive system. To effectively tackle these complexities, a unified approach to exosome analysis, encompassing both isolation and characterization, has been suggested. Techniques like microfluidic devices, magnetic bead-based methodologies, and aptamer-based separation can be employed for precise exosome isolation” (Page 19, right column, 1st para.), and “Successfully incorporating nucleic acid drugs into exosomes, identifying suitable host cells for their production, and ensuring stable ligand-receptor interactions for targeted delivery remain critical hurdles for clinical applications. Optimizing the combination of producer and target cells is essential for efficient therapeutic exosome production” (Page 20, left column, 3rd para.).
Schwarzenbach (Int. J. Transl. Med. 2024, 4, 247–261. Doi: 10.3390/ijtm4020015) teach “potential of exosomes as therapeutics and therapy targets in cancer patients” (title) and stated that
“For clinical application, several challenges have to be overcome. First, the cell type qualified to be used to for exosome extraction has to be identified, and then they have to be loaded with drugs. For example, the exosome source could be immune cells because exosomes released by antigen-presenting cells can provide therapeutic benefits though attenuating or stimulating the immune response. Exosomes derived from dendritic cells can activate T and B cells and carry MHC and so modulate antigen-specific T cell responses. A further challenge is to carry out a large-scale production of exosomes [92]. For example, Lamparski et al. developed a quick method for the production, purification and characterization of exosomes derived from antigen-presenting cells by ultrafiltration and ultracentrifugation. However, this technique still requires further testing with different types of cells. Next, effective loading approaches have to be standardized. Finally, studies regarding the potency and toxicology of exosomes are essential for bringing them into the clinic. Thus, a comprehensive evaluation of the optimal dose and drug distribution of exosomes in cancer treatment is urgently mandatory. To date, most studies have focused on exosomes in cell experiments, both in vitro and less often in mice. Hence, their efficacy and delivery to the recipient cells should be examined on long-term monitoring platforms and in vivo systems. Therefore, large multicenter and longer-term studies are required to achieve their clinical application” (Last para. of page 256 bridging to page 257)
“However, a major drawback of using exosomes as treatment strategies is that they contain thousands of unknown molecules (proteins, RNAs) with oncogenic and tumor suppressive characteristics. They are involved in different signaling pathways and may therefore have different effects on the tumor growth—in doing so, certain modes of actions may be predominant or less relevant. This is also the reason that it is difficult to predict their precise molecular mechanism and function in cancer. Their complex nature and, thus, the diversity of their natural compounds, may, therefore, complicate the therapeutic process of the disease. It is also not predictable how robustly and durably they influence the different signal pathways. Notably, exosomes can be engineered and used as anti-tumor delivery agents. Thus, engineering exosomes with known contents that counteract tumor-promoting functions may support the progress in cancer therapy” (2nd para. of page 257)
“Higher levels of exosomes are particularly secreted by the tumor cells in their environment than by normal cells. The cancer-derived exosomes may in turn be uptaken by normal cells that may then adopt cancerous characteristics. Therefore, a further challenge is to inhibit the tumor-derived exosome secretion and uptake by recipient cells, to restore tumor immunity and impair tumor progression. These investigations should also be carried out by large multicenter and longer-term studies to establish the efficacity of this approach” (3rd para. of page 257)
“Indeed, the exact efficiency of targeting of tumor-derived exosomes is also not predicable since they do not only contain tumor-stimulatory components but also tumorsuppressive components. The inhibition of these tumor-suppressive components may possibly have unforeseeable effects on the cancer therapy by inhibiting other signal pathways that are important for the fight against cancer, e.g., the immune system” (4th para. of page 257).
2. The use of any amount of exosomes derived from any tissue carrying any cargo for treating Polycystic ovary syndrome (PCOS) via any administration routes is unpredictable before the effective filing date of the claimed invention. Liu et al (International Journal of Nanomedicine 2026:21 574044, Doi: 10.2147/IJN.S574044) discuss “the mechanisms by which exosomes may ameliorate PCOS, including suppression of chronic low-grade inflammation, enhancement of mitochondrial function, inhibition of apoptosis, modulation of angiogenesis, and improvement of metabolic disturbances. However, translating these promising findings into clinical practice faces significant challenges. The main obstacles include lack of standardization, high production costs, and limited clinical data to confirm safety and efficacy. Addressing these issues could pave the way for mechanism-based, personalized exosome treatments and offer new approaches for managing PCOS” (Abstract).
Liu et al teach “Another important research direction in exosome therapy for PCOS is the choice of the administration route, as shown in Figure 4. Currently, the most common routes of administration are intravenous and ovarian injections. Intravenous injection delivers exosomes through the bloodstream, allowing their distribution to multiple organs such as the liver, fat, muscles, and ovaries. This route is more effective for treating metabolic abnormalities associated with PCOS, including insulin resistance and metabolic syndrome. However, this method suffers from an inadequate targeting. By contrast, ovarian injection directly delivers exosomes into the ovarian tissue or surrounding ovarian region, resulting in a significantly higher concentration of exosomes in the ovaries. This method offers greater targeting specificity and is effective in restoring normal ovarian function. However, studies on its effects on systemic metabolic disorders are limited. Therefore, selecting an appropriate route of administration is a key aspect of personalized treatment” (Page 12, 5th para.)
Liu et al teach “Despite the promising potential of exosome-based therapies for PCOS, some challenges and limitations remain in translating this approach into clinical practice. Exosomes have lower immunogenicity than cell transplants, but they are not completely risk-free. Exosomes from different sources may carry proteins or membrane antigens that could trigger immune reactions. Intravenously injected exosomes are often taken up by the liver and kidneys, which can lower their concentration at the target site, reducing effectiveness and possibly causing side effects in other organs. Local injections, such as into the ovary, improve targeting, but their effects on the whole body need more clinical study. Off-target effects are another concern. The miRNAs, proteins, or other molecules in exosomes can affect non-target cells. For example, when exosomes regulate the PI3K-AKT signaling pathway, they are intended to improve insulin sensitivity and metabolism in the ovaries or adipose tissue, but they may also affect the liver, heart, or muscle cells. This can abnormally activate or inhibit cell proliferation, apoptosis, and glucose or lipid metabolism, potentially leading to liver steatosis, cardiac myocyte hypertrophy, or skeletal muscle metabolic disorders. In addition, exosome preparation lacks standardized protocols. Exosomes from different sources or prepared using different methods vary in the types and concentrations of active molecules, which may further increase the risk of affecting non-target tissues. Therefore, in the study and clinical application of exosome therapy for PCOS, careful evaluation of in vivo distribution and off-target effects is essential to ensure safety and control. The clinical application of exosomes is not only limited by uncertainties regarding their safety, in vivo distribution, and off target effects, but also faces significant challenges in production and regulation. Current isolation techniques include ultracentrifugation, ultrafiltration, precipitation, immunoaffinity capture, and size-exclusion chromatography, each of which yields exosomes with varying purity and quantity. The lack of standardized good manufacturing practices for exosome processing and characterization remains a major obstacle to their clinical translation. For example, ultracentrifugation may break some exosomes or cause proteins to clump together, while immunoaffinity capture, though very specific, may collect exosomes from only certain subgroups, making the results less representative. Encouragingly, an increasing number of studies are focusing on improving and standardizing exosome production, isolation, and downstream purification. In addition, as a novel biological product, the clinical application of exosomes is also limited by regulatory barriers, including complex approval procedures, lengthy review processes, and a lack of clear guidelines. Addressing these production and regulatory issues is crucial for the safe and effective clinical application of exosome therapies. Future research should systematically investigate how exosomal heterogeneity influences therapeutic outcomes in PCOS. Specifically, studies are needed to compare exosomes derived from different cellular sources, isolated through distinct purification methods, or produced under varying culture conditions, as these factors markedly affect their molecular cargo and biological activity. Additionally, the disease status of the donor tissue may alter exosome composition and function, potentially leading to differential therapeutic efficacy. Addressing these dimensions of heterogeneity will be essential for identifying the most effective exosome populations, optimizing manufacturing protocols, and ultimately advancing exosome-based therapies toward clinical translation in PCOS.” (Page 12 to page 13).
3. The use of any amount of exosomes and extracellular matrix (ECM) components(growth factors, cytokines etc.) derived from any tissue for treating ovarian insufficiency via any administration routes is unpredictable before the effective filing date of the claimed invention: Yang et al (Reproductive Biology and Endocrinology (2026) 24:12 Doi: 10.1186/s12958-025-01514-9) teach “Delivery routes explored include intravenous (IV), intraperitoneal (IP), and intraovarian (local) injection. IV infusion is most common in preclinical ovarian studies, and a first-in-human trial in ovarian insufficiency has selected IV delivery (single infusion) for simplicity, safety, and cost. Nevertheless, IV delivery warrants careful biodistribution assessment to ensure effective ovarian exposure. By analogy, IV-infused MSCs exhibit a pronounced pulmonary first-pass effect (> 80% initially lodging in the lung microvasculature with 24 h persistence), with only a small fraction reaching distal organs. In contrast, locally injected MSC-Exos tend to remain within the ovary rather than distributing systemically. The clear benefit of intraovarian delivery is maximal ovarian enrichment of Exosomes and higher efficacy in restoring function. However, a key safety consideration is that the human ovary lacks the protective “cystic” bursa seen in rodents; consequently, intraovarian injection would entail direct deposition into the stromal or medullary parenchyma, and excessive injection volume or pressure may damage the fragile ovarian architecture. In preclinical POI studies, IP administration of Exosomes is far less common than IV or intraovarian delivery, and while IP can convey therapeutic Exosomes to ovaries, current evidence is too sparse to establish its comparative potency relative to the other routes” (Page 13, left column, 2nd para.)
Gu et al (Gu et al. Journal of Ovarian Research (2024) 17:139 Doi:10.1186/s13048-024-01448-7) teach “Ovarian fibrosis, characterized by the excessive proliferation of ovarian fibroblasts and the accumulation of extracellular matrix (ECM), serves as one of the primary causes of ovarian dysfunction. Despite the critical role of ovarian fibrosis in maintaining the normal physiological function of the mammalian ovaries, research on this condition has been greatly underestimated, which leads to a lack of clinical treatment options for ovarian dysfunction caused by fibrosis.” (Abstract). Gu et al teach “the TGF-β signaling pathway has multiple functions in the mammalian ovary. It regulates the recruitment of primordial follicles and the FSH sensitivity of growing follicles in an inhibitory manner. In addition, TGF-β is able to regulate follicular development, ovulation and COC expansion, and luteinisation after ovulation through its downstream Smad signaling pathway. Abnormally elevated levels of TGF-β1 in the ovary can lead to follicular dysplasia and ovulation failure. TGF-β is pivotal in tissue fibrosis, mediating this process through classical Smad-dependent or non-Smad pathways. Overexpression of TGF-β induces epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition, contributing to the onset of fibrotic diseases like lung, kidney, and liver fibrosis” (Page 2, right column, 2nd para). Gu et al teach “the excessive deposition of ECM may lead to ovarian fibrosis and functional impairment . Research has revealed that platelet endothelial aggregation receptor 1 in fibroblasts promotes lung fibrosis by regulating the proliferation of activated fibroblasts and ECM deposition . The accumulation of extracellular matrix (ECM) increases progressively during follicular development and ovary aging. ECM plays a crucial role in promoting fibrosis, making it a key contributing factor in the development of abnormal fibrosis in the ovary . Therefore, the elevated ECM levels in the ovary exacerbate the progression of aberrant fibrosis” (Page 3, left column, 1st para).
The specification lacks sufficient variety of species to reflect this variance in the genus showing the contemplated medical effect of any particular amount of exosomes and extracellular matrix (ECM) components to treat any and all ovarian disorder disorders or conditions. The specification does not provide sufficient descriptive support for the myriad of embodiments embraced by the claims.
The skilled artisan cannot envision the detailed chemical structure of the broadly recited any amount of exosomes and extracellular matrix (ECM) components to treat any ovarian disorder or condition other than those described in the specification, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the claimed method. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v.Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Thus, it is concluded that the written description requirement is not satisfied for the broadly claimed genus of methods for treating an ovarian disorder or condition.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 20 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 20 does not further limit claim 8. Claim 20 which depends on claim 8 requires “administering a single unit-dose of the first pharmaceutical composition to the subject or more than one unit-dose of the first pharmaceutical composition to the subject” while claim 8 recites “administering one or more unit-doses of a first pharmaceutical composition”. Thus, both claims appear to be intended to encompass embodiments where one or more unit-doses of the first pharmaceutical composition is administered to the subject. As such, it is not seen how claim 20 as currently written further limits claim 8.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1-4, 8, 20 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al (Pub. No.: US 2020/0289574 Al, Pub. Date: Sep. 17, 2020) in view of Vitti (Pub. No.: US 2022/0133803 Al, Pub. Date: May 5, 2022) (Applicant’s own work).
Claim interpretation:
According to the instant disclosure, “the term permeate media composition refers to a solution and its contents that have passed through a membrane filter. In various aspects, the permeate media composition is an exosome composition, wherein the permeate media composition comprises at least one exosome isolated from a mesenchymal stem cell, and at least one component isolated from an extracellular matrix (e.g., an "ECM component"). As used herein, the terms "exosome composition" and "permeate media composition" are used synonymously” (see the specification [0043], page 8), and “ the term 'filtrate' and 'permeate' are used interchangeably to describe contents of a mixture that have passed through a filter (i.e., a filter in a tangential flow filtration system)” (see the specification [0138], page 48). Thus, "exosome composition" and "permeate media composition" are interpreted synonymously, and the term 'filtrate' and 'permeate' are used interchangeably.
According to the instant disclosure, the term "retentate media composition" refers to a components of a solution or mixture that have not passed through and are thus retained by a membrane filter. In various aspects, the retentate media composition is an MSC composition comprising at least one mesenchymal stem cell, wherein the MSC composition is free of any extracellular matrix or fragments thereof. In various aspects, the retentate media composition may comprise up to 50% by weight mesenchymal stem cells. As used herein, the terms "retentate media composition" and "MSC composition" are used synonymously (see the specification [0044], page 8).Thus, "retentate media composition" and "MSC composition" are interpreted synonymously.
Regarding to claim 1 and 40, Brown et al teach “Methods and compositions for stimulating ovarian function in a patient suffering from premature ovarian failure and for decreasing recurrent spontaneous abortion are disclosed” (Abstract). Brown et al teach “ a method of stimulating ovarian function in a patient suffering from premature ovarian failure comprising the steps of: a) obtaining peripheral blood; b) isolating platelet rich plasma, and/or platelet lysate; c) quantifying growth factor content of said platelet rich plasma and/or platelet lysate; ……. e) administering said growth factors locally into ovarian tissue in a patient in need of treatment” (e.g., claim 1, page 6), wherein said growth factors are exosomes (e.g., claim 3, page 6), and growth factors associated with platelet rich plasma and/or platelet lysate are selected from EGF, IGF, VEGF, PDGF, activin A and combinations thereof (e.g., claim 2, page 6).
Brown et al do not teach permeate media composition. Vitti cures the deficiency.
Vitti teaches method for isolating large quantities of viable, undamaged exosomes from liquid, cell-free mesenchymal stem cell cultures using tangential flow filtration (Abstract). The plurality of exosomes is isolated from the liquid cell-free culture medium by: filtering the liquid cell-free culture medium through a first hollow fiber filter having a pore size of about 0.1 µm to about 1.0 µm to obtain a first permeate; and subjecting the first permeate to diafiltration through a second hollow fiber filter having a pore size of about 30 kD to 600 kD to obtain a retentate ([0009], page 1). The method further comprises filtering the first permeate through an intermediate hollow fiber filter having a pore size of about 0.45 µm to about 2.0 µm, to obtain a second permeate, and then filtering the second permeate through the second hollow fiber to obtain the permeate. In specific embodiments, the intermediate hollow fiber filter has a pore size of about 0.1 µm ([0011], page 1).
PNG
media_image1.png
1101
783
media_image1.png
Greyscale
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Brown et al by using method and system for isolation of mesenchymal stem cell exosomes as taught by Vitti as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Vitti teaches isolating large quantities of viable, undamaged exosomes from liquid, cell-free mesenchymal stem cell cultures using tangential flow filtration (Abstract). Vitti teaches “it has also been discovered that the exosomes isolated by this process are substantially undamaged, of high yield, free of debris and contaminants, and of therapeutic use-quality” ([0007], page 1) and “Exosomes carry protein, lipid, and RNA loads from the cell, and as such, perform a functional role that mediates cellular-cell communication and cellular immunity. …… exosomes are a form of "natural" drug delivery, and do not elicit acute immune rejection, they have been loaded ex vivo with certain therapeutic agents and targeted to deliver their therapeutic loads to specific cells types” ([0002] page 1). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Vitti was successful in preparations of exosomes that are homogenous, intact, free of contaminants, and concentrated enough to provide commercially viable and therapeutic yields.
Regarding to claim 2, 3, 4, Brown et al teach “administering said growth factors locally into ovarian tissue in a patient in need of treatment” (e.g., claim 1, page 6). Brown et al teach growth factors associated with platelet rich plasma and/or platelet lysate are selected from EGF, IGF, VEGF, PDGF, activin A and combinations thereof (e.g., claim 2, page 6).
Regarding to claims 8 and 20, Brown et al teach e) administering said growth factors locally into ovarian tissue in a patient in need of treatment” (e.g., claim 1, page 6), wherein said growth factors are exosomes (e.g., claim 3, page 6).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHOA NHAT TRAN whose telephone number is (571)270-0201. The examiner can normally be reached M-F (9-5).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, PETER PARAS can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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.
/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
Prosecution Insights