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 Status
The amendments filed 09/25/2024 are entered. Claims 3-8 are pending and under examination.
Priority
The application is a 371 application, filed 09/25/2024, of PCT application PCT/JP2023/012062, filed 03/26/2023, which claims priority benefits from Foreign Application No. JP2022-051095, filed 03/28/2022.
However, the certified copy of the foreign priority document is not translated to English; therefore, priority benefit cannot be determined form the foreign priority document.
Therefore, the effective filing date of this application is 03/26/2023, the filing date of the PCT/JP2023/012062.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 09/25/2024 is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
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 5 and 8 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.
Claims 5 and 8 recite “using monensin or a monensin salt” but due to this limitation’s location in the sentence and the sentence structure, it is unclear if the monensin or monensin salt is added in the exosome collection step, in the chondrocyte culture step, and/or the cell immortalization step, as applicable to the claim.
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.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Ross (US 2019/0000886 Al, Method of Treatment of Osteochondral Defects; published 01/03/2019) in view of Katoh et al (EP 3954761 A1, Chondrocyte culture with high tissue regeneration ability; filed 04/08/2020), Li et al (2013) (Li et al, MicroRNA expression profiling and target genes study in congenital microtia; published 2013), and Duan et al (Duan et al, Recent progress on the role of miR-140 in cartilage matrix remodeling and its implications for osteoarthritis treatment, published 2020).
Regarding claim 3, Ross et al teaches a method for producing a pharmaceutical composition including chondrocyte-derived exosomes (Abstract).
Ross et al defines "exosomes" as a type of extracellular membrane-enclosed vesicle, which contains molecular constituents of the cell it was secreted from (para 0025). Ross et al further teaches a pharmaceutical composition comprising of membrane-enclosed vesicle comprising, for example, miR-140 (para 0071), which fits the definition of an exosome (para 0072).
Ross et al further teaches the method of exosome preparation by culturing the cell that produces the exosome and collecting the exosome from the culture media (para 0079-0080).
Ross et al does not explicitly teach chondrocyte-derived exosomes comprising miR-140 in one embodiment. Ross et al does not explicitly teach auricular chondrocyte. Ross et al does not explicitly teach culturing chondrocyte with estrogen.
However, Kato et al teaches a method of chondrocyte culture, wherein the source of the cell is cartilage tissue, which can be auricular cartilage and other cartilage sources (para 0016).
Kato et al further teaches the chondrocyte culture expresses and retains miRNAs, particularly preferably miR140, including miR-140-3p and miR-140-5p (para 0092-0093).
Li et al (2013) particularly teaches the upregulation of miR-140-3p in congenital microtia tissues (p. 484, section 3.1. MicroRNA expression array), wherein the tissue samples are auricular cartilage and soft tissue (p. 484, section 2.1. Sample collection: patients and normal controls).
Ross, Kato et al, and Li et al (2013) do not explicitly teach culturing chondrocyte with estrogen.
However, Duan et al teaches estrogen upregulates miR-140 expression levels in chondrocytes since the miR-140 promoter contains estrogen receptor response elements (p. 4, col. 2, para. 1).
Duan et al further teaches exosomes derived from miR-140-overexpressing cells and miR-140-encapsulated exosomes could be used to promote MSC chondrogenesis or inhibit cartilage matrix degradation for osteoarthritis (OA) therapy (p. 5-7, section: Exosomal delivery of miR-140 in OA treatment). Duan et al additionally teaches that miR-140 is evolutionarily conserved among vertebrates and expressed in chondrocytes, and regulates chondrogenesis of mesenchymal stem cells (Abstract and p. 2, col. 2, para. 2). Both underexpression and overexpression of miR-140 play a role in diseases associated with cartilage destruction (p. 2, col. 2, para. 2). Duan et al teaches that these miRNAs are significantly downregulated in chondrocytes from knee osteoarthritis (p. 3, col. 2, para. 2).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to culture auricular chondrocyte with estrogen to produce exosomes containing miR-140 and formulate these exosomes into a pharmaceutical composition because of the known pharmaceutical benefits of exosome-delivered miR-140 and the link between estrogen upregulating miR-140 expression, as taught by Duan et al, and the production of miR-140 and exosome by auricular cartilage, as taught by Ross in view of Kato et al and Li et al (2013).
One skilled in the art, before the effective filing date of the instant application, would be motivated to produce miR-140-containing exosomes for its pharmaceutical utility, specifically from auricular chondrocytes because it is a source of miR-140 that could be stimulated to highly express miR-140 using estrogen. Although articular cartilage may be the most highly studied, and auricular chondrocytes have not explicitly been used to produce miR-140-containing exosomes, the references together teach that auricular chondrocytes can also reasonably feasibly be used to produce miR-140-containing exosomes. Although the references do not explicitly teach culturing the chondrocytes with estrogen, one skilled in the art, before the effective filing date of the instant application, would be motivated to do so for the advantage of stimulating miR-140 expression during cell culture.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success because miR-140 expression is essentially linked to chondrocytes, especially in the presence of estrogen, and chondrocytes have been used to produce exosomes, which carry the microRNA of its source cells. MiR-140 is present in all chondrocytes, which includes auricular chondrocytes, and particularly, miR-140 has been shown to be overexpressed in auricular cartilage of patients with microtia, which is a congenital abnormality of the outer ear where auricular cartilage resides. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success that estrogen can stimulate chondrocyte in culture to express miR-140 since the miR-140 promoter in chondrocytes have a direct response to estrogen, as taught by Duan et al.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Ross (US 2019/0000886 Al, Method of Treatment of Osteochondral Defects; published 01/03/2019) in view of Katoh et al (EP 3954761 A1, Chondrocyte culture with high tissue regeneration ability; filed 04/08/2020), Li et al (2013) (Li et al, MicroRNA expression profiling and target genes study in congenital microtia; published 2013), and Duan et al (Duan et al, Recent progress on the role of miR-140 in cartilage matrix remodeling and its implications for osteoarthritis treatment, published 2020), as applied to claim 3 above, and further in view of Li et al (2021) (Li et al, MicroRNAs target on cartilage extracellular matrix degradation of knee osteoarthritis; published 02/01/2021).
The teachings of the references regarding claim 3 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 4, the previous references do not teach the estrogen is estradiol.
However, Li et al (2021) teaches estradiol (E2) can directly upregulate the expression of miR-140 in chondrocytes (p. 1191, section: MiR-140).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to specifically use estradiol in the chondrocyte culture since estradiol is a specific form of estrogen that serves the purpose of upregulating miR-140 in chondrocytes.
Since estrogen is a broad class of hormones, one skilled in the art, before the effective filing date of the instant application, would be motivated to choose the specific type of estrogen that has been shown to upregulate miR-140 in chondrocytes.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success that estradiol can stimulate chondrocyte in culture to express miR-140 since the miR-140 promoter in chondrocytes have a direct response to estrogen, as taught by Duan et al, and Li et al (2021) shows that estradiol in particular regulates miR-140.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Ross (US 2019/0000886 Al, Method of Treatment of Osteochondral Defects; published 01/03/2019) in view of Katoh et al (EP 3954761 A1, Chondrocyte culture with high tissue regeneration ability; filed 04/08/2020), Li et al (2013) (Li et al, MicroRNA expression profiling and target genes study in congenital microtia; published 2013), and Duan et al (Duan et al, Recent progress on the role of miR-140 in cartilage matrix remodeling and its implications for osteoarthritis treatment, published 2020), as applied to claim 3 above, and further in view of Hayashi et al (Hayashi et al, Exosomal MicroRNA Transport from Salivary Mesenchyme Regulates Epithelial Progenitor Expansion during Organogenesis; published 2017), as evidenced by von Osch et al (von Osch et al, Cells for Cartilage Regeneration, Chapter 4; published 2020).
The teachings of the references regarding claim 3 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 5, the previous references do not teach the use of monensin or a monensin salt.
However, Hayashi et al teaches that monensin is a biologically safe but effective way to increase exosome release in a mesenchymal cell line (p. 97, col 1-2), and as evidenced by van Osch et al, chondrocytes, such as auricular cartilage, are derived from mesenchymal cells (p. 54, section: 4.1 Auricular chondrocytes in their natural environment, para. 1).
Duan et al further teaches many advantages of exosomes as a cargo delivery mechanism (p. 5, section: Exosomes), and particularly for microRNA delivery (p. 6, section: miR-140 delivery by exosomes).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that after the chondrocytes were stimulated with estrogen to express miR-140, monensin could be added to the cell culture to stimulate miR-140-containing exosome release from the chondrocyte.
One skilled in the art, before the effective filing date of the instant application, would be motivated to add the monensin to promote exosome secretion, since exosome-bound microRNA is a more stable and safer form of microRNA delivery, as taught previously by Duan et al.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success since monensin is known to generally stimulate exosome release in various cells, and in particular has been used to stimulate mesenchymal cells, which is the progenitor of chondrocytes.
Claim 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Ross (US 2019/0000886 Al, Method of Treatment of Osteochondral Defects; published 01/03/2019) in view of Katoh et al (EP 3954761 A1, Chondrocyte culture with high tissue regeneration ability; filed 04/08/2020), Li et al (2013) (Li et al, MicroRNA expression profiling and target genes study in congenital microtia; published 2013), and Duan et al (Duan et al, Recent progress on the role of miR-140 in cartilage matrix remodeling and its implications for osteoarthritis treatment, published 2020), as applied to claim 3 above, and further in view of Hoffman et al (WO 2018208670 A1; filed 05/07/2018).
The teachings of the references regarding claim 3 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 6, the previous references do not explicitly teach immortalization of the cultured auricular chondrocytes, and further regarding claim 7, do not explicitly teach immortalization with SV40 or hTERT.
However, regarding claim 6, Hoffman et al teaches immortalizing cultured articular chondrocytes, and collecting exosomes from those immortalized cells (p. 6, lines 14-19). Regarding claim 7, Hoffman et al further teaches immortalization of mesenchymal stromal cells by transduction with SV40 (also called SV40T) or hTERT (p. 52, line 30-31).
Although Hoffman et al does not explicitly teach immortalizing auricular chondrocytes; however, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, that the immortalization technique using SV40 or hTERT is not exclusive to mesenchymal cells or articular chondrocytes. Rather, these cells are heavily studied models of mesenchymal cell line progenitors and chondrocytes, respectively; therefore, the immortalization technique is widely applicable, and particularly also applicable to auricular chondrocytes.
One skilled in the art, before the effective filing date of the instant application, would be motivated to immortalize the chondrocytes for the many general benefits of immortalizing cell lines used in pharmaceutical applications, and specifically, for the rapid and reproducible production of the miR-140-containing exosomes. One would be motivated to use SV40 or hTERT in particular since it has been taught in a method to immortalize cells used to produce exosomes.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success since these two cell immortalization techniques are broadly applicable to a variety of cell types.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Ross (US 2019/0000886 Al, Method of Treatment of Osteochondral Defects; published 01/03/2019) in view of Katoh et al (EP 3954761 A1, Chondrocyte culture with high tissue regeneration ability; filed 04/08/2020), Li et al (2013) (Li et al, MicroRNA expression profiling and target genes study in congenital microtia; published 2013), Duan et al (Duan et al, Recent progress on the role of miR-140 in cartilage matrix remodeling and its implications for osteoarthritis treatment, published 2020), and Hoffman et al (WO 2018208670 A1; filed 05/07/2018), as applied to claim 6 above, and further in view of Hayashi et al (Hayashi et al, Exosomal MicroRNA Transport from Salivary Mesenchyme Regulates Epithelial Progenitor Expansion during Organogenesis; published 2017), as evidenced by von Osch et al (von Osch et al, Cells for Cartilage Regeneration, Chapter 4; published 2020).
The teachings of the references regarding claim 6 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
The references, as previously discussed, teach a method of producing a pharmaceutical composition comprising of auricular chondrocyte-derived miR-140-containing exosome, wherein the chondrocyte is cultured in estrogen to stimulate miR-140 expression. In one embodiment through the claims, the chondrocytes are further explicitly cultured with monensin or a monensin salt to stimulate exosome release. In another embodiment, the chondrocytes are explicitly further immortalized. Regarding claim 8, the chondrocytes that are explicitly further immortalized are explicitly cultured with monensin or a monensin salt.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, for the reasons previously presented regarding the use of monensin to stimulate exosome release, to use monension to release the exosome from the chondrocyte, whether they are immortalized cells or not immortalized cells.
One skilled in the art, before the effective filing date of the instant application, would be motivated to use monension to help release the pharmaceutically important exosomes from their producing cells.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success since these methods of immortalization appear compatible with exosome production, and monensin would reasonably trigger exosome release from auricular chondrocytes, as previously discussed.
Prior Art Not Relied Upon
Savina et al (Exosome Release Is Regulated by a Calcium-dependent Mechanism in K562 Cells; published 2013)
Savina et al teaches monensin stimulates exosome release in a calcium-dependent mechanism, in a hematopoietic cell line model that releases exosomes (Abstract).
Schroit et al (US 2015/0241431 Al, Methods and Compositions for Isolating Exosomes, filed 02/27/2015)
Schroit et al teaches methods to isolate intact exosomes without damaging their morphological or functional properties (Abstract).
von Osch et al (Cells for Cartilage Regeneration, Chapters 4 and 6; published 2020); Chapter 4 previously presented as evidentiary reference.
von Osch et al teaches methods of isolating and expanding auricular chondrocytes (Chapter 4), and immortalizing chondrocytes (Chapter 6).
Yi et al (WO 2020231702 A1, Compositions and Methods Containing Exosomes, filed 05/06/2020)
Teaches mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into a variety of cell types, including chondrocytes (para. 0018). In some embodiments, exosomes are isolated from exosome secreting cells (para. 0031) where the cells could be derived from chondrocytes (para. 0034).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BONIRATH CHHAY whose telephone number is (571)272-0682. The examiner can normally be reached Mon-Thu 8AM-5PM EST.
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/BONIRATH CHHAY/Examiner, Art Unit 1645 May 28, 2026
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 1, 2026
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