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 .
Priority
The instant application is a national stage entry under 35 USC 371 of PCT/JP2022/024432, filed
17 June 2022. Acknowledgement is made of Applicant’s claim for foreign priority under 35 USC 119(a)-(d) to Japanese Application No. JP2021-102068, filed 18 June 2021. Receipt is acknowledged of certified copies of papers, in a non-English language, required by 37 CFR 1.55.
Status of the Claims
Applicant’s preliminary submission filed 18 December 2023 has been entered. Claims 1-12, 15, 17-19, 22, 25, 27, and 29 are pending. Claims 1-12, 15, 17-19, 22, 25, 27, and 29 have been amended, while claims 13-14, 16, 20-21, 23-24, 26, 28, and 30 have been cancelled without prejudice or disclaimer. Therefore, prosecution on the merits commences for claims 1-12, 15, 17-19, 22, 25, 27, and 29.
Claim Interpretation
Instant claim 29 is directed to a product, which utilize product-by-process language. The limitations of the process of production are considered only in so far as the process of production
imparts distinct structural or chemical characteristics or properties to the claimed product. Therefore, if
the product, as claimed, is the same or obvious over a product of the prior art (i.e. is not structurally or
chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art
product is made by a different process. See MPEP § 2113.
In the instant case, claim 29 further defines the multinucleated megakaryocyte cells as being derived from immortalized megakaryocytes. When defining the source of cells, the source of the cells is only considered in as far as the source defines the cell as having distinct biochemical or morphological
characteristics. In the instant case, the source of the multinucleated megakaryocyte cells does not impart a distinction to the multinucleated megakaryocyte cells.
Therefore, the claims will be interpreted as if multinucleated megakaryocyte cells derived from any source fulfills the limitation detailed in the instant claim.
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 25 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.
Regarding claim 25: The instant claim recites the limitation, “wherein the multinucleated megakaryocytes further comprise multinucleated megakaryocytes having a nuclear phase of 8N or more”. As parent claim 22 already requires the multinucleated megakaryocytes to have a nuclear phase of 16N or more, instant claim 25 does not further limit the claim from which it depends. It is of note that 8N is a lower nuclear phase than 16N.
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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 22, 25, 27, and 29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a nature-based product without significantly more.
Independent claim 25 is directed to a cell population comprising multinucleated megakaryocytes, wherein the multinucleated megakaryocytes comprise multinucleated megakaryocytes having a nuclear phase of 16N or more, and a percentage of a number of the multinucleated megakaryocytes having a nuclear phase of 16N or more in the cell population is in a range of 20% or more.
Instant claim 29 comprises a product-by-process limitation, as can be observed in the Claim Interpretation section above and is incorporated in its entirety herein.
The test for 101 eligibility of judicial exceptions can be found at MPEP § 2106:
“First, the claimed invention must be to one of the four statutory categories. 35 U.S.C. 101 defines the four categories of invention that Congress deemed to be the appropriate subject matter of a patent: processes, machines, manufactures and compositions of matter.”
“Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception. The judicial exceptions (also called "judicially recognized exceptions" or simply "exceptions") are subject matter that the courts have found to be outside of, or exceptions to, the four statutory categories of invention, and are limited to abstract ideas, laws of nature and natural phenomena (including products of nature). Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 216, 110 USPQ2d 1976, 1980 (2014) (citing Ass'n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 589, 106 USPQ2d 1972, 1979 (2013).”
“The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). This framework, which is referred to as the Mayo test or the Alice/Mayo test, is discussed in further detail in subsection III, below. The first part of the Mayo test is to determine whether the claims are directed to an abstract idea, a law of nature or a natural phenomenon (i.e., a judicial exception). Id. If the claims are directed to a judicial exception, the second part of the Mayo test is to determine whether the claim recites additional elements that amount to significantly more than the judicial exception. Id. citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966). The Supreme Court has described the second part of the test as the "search for an 'inventive concept'". Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).”
Examiners should determine whether a claim satisfies the criteria for subject matter eligibility by evaluating the following steps outlined in a flow chart at MPEP 2106(III) and 2106.04(II)(A):
Step 1: is the Claim to a process, machine, manufacture or composition of matter? If Yes, proceed to Step 2A;
Step 2A, prong one: Is the Claim directed to a law of nature, a natural phenomenon (product of nature), or an abstract idea? If Yes, proceed to Step 2A, prong two;
Step 2A, prong two: Does the claim recite additional elements that integrate the judicial exception into a practical application? If No, proceed to Step 2B;
Step 2B: Does the claim recite additional elements that amount to significantly more (an inventive concept) than the judicial exception? If No, the claim is not eligible subject matter under 35 USC 101.
With regard to Step 1: YES, the claims are each directed to a composition of matter, or product.
With regard to Step 2A, prong one: YES, the instant claim 1 is directed to a population of multinucleated megakaryocytes, which are nature-based products. Accordingly, the claimed multinucleated megakaryocytes are compared to the closest naturally occurring counterpart, which are multinucleated megakaryocytes, per se. Thus, there is no marked difference between the claim and product of nature. See, for example, Pages 787-788 and Figure 1 in Machlus et al (J Cell Biol, 2013), wherein a percentage of the naturally-occurring multinucleated megakaryocytes have a nuclear phase of 16N or more.
With regard to Step 2A, prong two: No, the claims do not include any additional elements that integrate the judicial exceptions into a practical application. Integration into a practical application requires additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception.
The claims do not modify or transform the naturally occurring multinucleated megakaryocytes, nor apply the multinucleated megakaryocytes for a particular treatment or medical condition, nor imposes a meaningful limit on the multinucleated megakaryocytes recited therein.
With regard to Step 2B: No, the claim does not provide any additional elements that amount to significantly more (an inventive concept) than the judicial exception. It is of note that the percentages of multinucleated megakaryocytes having a specific nuclear phase within the population does not alter the multinucleated megakaryocytes, per se.
Taken together, the claims encompass natural products. The judicial exceptions are not integrated into practical applications as iterated above. The claim does not include additional elements
that are sufficient to amount to significantly more than the judicial exception as iterated above.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 22, 25, 27, and 29 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Wu (WO 2018/005417 A1).
Wu discloses a population of multinucleated megakaryocytes, wherein the population comprises 67% of multinucleated megakaryocytes having a nuclear phase of 8N, 28% of multinucleated megakaryocytes having a nuclear phase of 16N, and 5% of multinucleated megakaryocytes having a nuclear phase of 32N (Abstract; Paragraph [0063]).
Accordingly, Wu anticipates the claims as follows:
Regarding claims 22, 25, and 27: Wu discloses a population of multinucleated megakaryocytes, wherein the population comprises 67% of multinucleated megakaryocytes having a nuclear phase of 8N (claim 25), 28% of multinucleated megakaryocytes having a nuclear phase of 16N (claim 22), and 5% of multinucleated megakaryocytes having a nuclear phase of 32N (claim 27). This therefore reads on the cell population of the instant claims.
Regarding claim 29: Instant claim 29 comprises product-by-process language. The effect
of the product-by-process language is discussed above – see Claim Interpretation – and is incorporated herein in its entirety. As such, the source of the multinucleated megakaryocytes does not impact the multinucleated megakaryocytes, per se, and thereby draws to the cell population detailed in instant claim 22.
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 1-2, 4-9, 12, 15, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Eto et al (US 2019/0048317 A1, of record on IDS filed 02 July 2025) in view of Elagib et al (Blood, 2019, of record on IDS filed 18 December 2023).
Eto et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with a publication date of 14 February 2019. Elagib et al is considered prior art under 35 USC 102(a)(1).
Regarding claims 1-2, 6, 8, and 17: Eto et al disclose a highly functional platelet production promoting agent comprising AhR inhibitors and ROCK inhibitors (Abstract; Paragraph [0118]).
As such, Eto et al disclose a method for obtaining multinucleated megakaryocytes, wherein the method comprises contacting megakaryocyte progenitor cells with the platelet production promoting agent and a protein encoded by a cancer gene, a polycomb gene, or an apoptosis suppressor gene, wherein the megakaryocyte progenitor cells become multinucleated megakaryocytes (Paragraphs [0077]-[0081], [0110]-[0111], [0115], [0129], [0155], [0166], [0248]).
Eto et al do not disclose that the megakaryocyte progenitor cells are multinucleated in the presence of harmine, as required by instant claim 1.
Elagib et al, however, disclose that the treatment of megakaryocyte progenitors with harmine results in multinucleated megakaryocytes having an enhanced in vitro and in vivo platelet release (Page 2). Elagib et al further disclose that the harmine treatment can be combined with an AhR inhibitor (Page 2).
Therefore, it would have been prima facie obvious to have modified the method of Eto et al such that the megakaryocyte progenitor cells are further contacted with harmine, as detailed in Elagib et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to treat the megakaryocyte progenitor cells with harmine, as it independently enhances platelet release in multinucleated megakaryocytes and increases morphogenesis when combined with AhR inhibitors, and would have had a reasonable expectation of success given that the disclosures of Eto et al and Elagib et al are concerned with the production of multinucleated megakaryocytes having an enhanced platelet production. See MPEP § 2143(I)(G).
Consequently, Eto et al as modified by Elagib et al render obvious a method for obtaining multinucleated megakaryocytes having an enhanced platelet production, the method comprising contacting megakaryocyte progenitor cells with an AhR inhibitor (claims 2, 6), a ROCK inhibitor (claim 8), harmine, and a protein encoded by a cancer gene, a polycomb gene, or an apoptosis suppressor gene (claim 17). This therefore renders obvious the method of instant claim 1.
Regarding claims 4-5: Following the discussion of claim 1, Eto et al further disclose that the megakaryocyte progenitor cells are first expanded in culture medium that does not comprise the AhR or ROCK inhibitors (claim 4), and are then switched to a culture medium comprising the AhR inhibitor and ROCK inhibitor (claim 5) (Paragraphs [0111]-[0114], [0129], [0190]-[0203], [0236]-[0248]). This therefore reads on the method of the instant claims.
Regarding claim 7: Following the discussion of claim 2, Eto et al further disclose that the AhR inhibitor is GNF-351 (Paragraphs [0014], [0016], [0039], [0049], [0059], [0063], [0105]-[0107], [0116], [0248]). This therefore reads on the method of the instant claim.
Regarding claim 9: Following the discussion of claim 2, Eto et al further disclose that the ROCK inhibitor is Y-39983 (Paragraphs [0015]-[0016], [0040], [0050], [0063], [0114]-[0116], [0248]). This therefore reads on the method of the instant claim.
Regarding claims 12 and 15: Following the discussion of claim 1, Eto et al further disclose that the multinucleated megakaryocytes have a genome that is 16 times to 32 times larger than that of normal cells – or a nuclear phase of 16N to 32N (Paragraph [0078]).
The combination of Eto et al and Elagib et al fail to teach that the population of multinucleated megakaryocytes comprises at least 20% of multinucleated megakaryocytes having a nuclear phase of 16N or more and 5-50% of multinucleated megakaryocytes having a nuclear phase of 32N or more, as required by instant claims 12 and 15.
However, it would have been prima facie obvious to have modified the method of Eto et al in view of Elagib et al such that the generated population of multinucleated megakaryocytes comprises 20% 16N multinucleated megakaryocytes and 5% 32N multinucleated megakaryocytes. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to ensure the population comprised those percentages, as megakaryocytes having a nuclear phase of 16N and 32N indicates that they have been successfully multinucleated. Furthermore, the ordinary artisan would have had a reasonable expectation of success given that Eto et al disclose that the generated multinucleated megakaryocytes have a nuclear phase of 16N and 32N, and it would not have been outside the skillset of the ordinary artisan to modify the proportion of 16N and 32N multinucleated megakaryocytes within the population via well-known sorting and/or fractionation techniques. See MPEP § 2143(I)(G) and MPEP § 2144.05.
Consequently, Eto et al as modified by Elagib et al render obvious a method for obtaining multinucleated megakaryocytes having an enhanced platelet production, wherein the generated population of multinucleated megakaryocytes comprises 20% of multinucleated megakaryocytes having a nuclear phase of 16N (claim 12) and 5% of multinucleated megakaryocytes having a nuclear phase of 32N (claim 15). This therefore renders obvious the method of the instant claims.
Regarding claim 18: Following the discussion of claim 1, Eto et al further disclose that the megakaryocyte progenitor cells are immortalized megakaryocytes (Paragraph [0079], [0111], [0129], [0150], [0169]-[0203], [0236]). This therefore reads on the method of the instant claim.
Regarding claim 19: Following the discussion of claim 1, Eto et al further disclose that the multinucleated megakaryocytes induced from megakaryocyte progenitor cells produce platelets (Paragraphs [0003], [0053], [0079], [0155]). This therefore renders obvious the method of the instant claim for the same reasons as discussed in the rejection of instant claim 1.
Claims 1-12, 15, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Eto et al (US 2019/0048317 A1, of record on IDS filed 02 July 2025) in view of Elagib et al (Blood, 2019, of record on IDS filed 18 December 2023), and further in view of Ohtori et al (US 2023/0030814 A1, of record on IDS filed 18 December 2023).
The discussion of Eto et al as modified by Elagib et al regarding claims 1-2 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Eto et al as modified by Elagib et al render obvious claims 1-2, 4-9, 12, 15, and 17-19. Ohtori et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 12 December 2019.
Regarding claims 3 and 10-11: As aforementioned in the discussion of claims 1-2 above, Eto et al as modified by Elagib et al render obvious a method for obtaining multinucleated megakaryocytes having an enhanced platelet production, the method comprising contacting megakaryocyte progenitor cells with an AhR inhibitor, a ROCK inhibitor, harmine, and a protein encoded by a cancer gene, a polycomb gene, or an apoptosis suppressor gene.
The combination of Eto et al and Elagib et al fail to teach that the megakaryocyte progenitor cells are contacted with a myosin 2 inhibitor, as required by instant claims 3 and 10.
Ohtori et al, however, disclose the multinucleation of megakaryocytes via contacting megakaryocyte progenitor cells with an AhR inhibitor, a ROCK inhibitor, a myosin 2 inhibitor, and a protein encoded by a cancer gene, a polycomb gene, or an apoptosis suppressor gene (Paragraphs [0049]-[0050], [0080], [0104], [0106]-[0109]). Ohtori et al further disclose that the myosin 2 inhibitor is blebbistatin (Paragraph [0104]).
Therefore, it would have been prima facie obvious to have modified the method of Eto et al in view of Elagib et al such that the megakaryocyte progenitor cells are further contacted with the myosin 2 inhibitor, blebbistatin, as detailed in Ohtori et al. One of ordinary skill before the effective filing date of the invention would have been motivated to contact the megakaryocyte progenitor cells with an inhibitor known to induce multinucleation within the megakaryocyte progenitor cells, and would have had a reasonable expectation of success given that the disclosures of both Eto et al and Ohtori et al are concerned with the generation of multinucleated megakaryocytes utilizing methods that would require minimal adaptation. See MPEP § 2143(I)(G).
Consequently, Eto et al as modified by Elagib et al and Ohtori et al render obvious a method for obtaining multinucleated megakaryocytes having an enhanced platelet production, the method comprising contacting megakaryocyte progenitor cells with an AhR inhibitor, a ROCK inhibitor, a myosin 2 inhibitor (claim 10), harmine, and a protein encoded by a cancer gene, a polycomb gene, or an apoptosis suppressor gene (claim 3). As the myosin 2 inhibitor is blebbistatin, this therefore renders obvious the method of instant claim 11.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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