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 .
Status of the Claims
Claims 21-22 ,27, 29, 36-37, 42, 50-51, 53, 57-58, 61, 74, 76, 78, 85, 87, 92 and 126 are pending and examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US2022/023356, filed on April 4, 2022. The instant application claims benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) to U.S. provisional applications 63/170,405, filed on April 2, 2021 and 63/240,739, filed on September 3, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 9, 2024 is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
Claim Objections
Claim 57 is objected to because of the following informalities: claim 57 recites “length, width, and/or width of an approach region” in line 4. It is noted that the instant specification refers to “length, width, and/or width or an approach region” in Paras. [0020], [0034], and [0042] and “length, depth, and width of the approach region” in Para. [0148]. It is recommended that Applicant amend to either remove one recitation of width or correct the typographical error.
Claim 74 is objected to because of the following informalities: Claim 74 recites “…multiple reprogramming factors are cable of entering…” in line 3. This is considered to be a typographical misspelling of “capable”. It is recommended that Applicant amend to correct the spelling of capable.
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 57, 74, 76, 78, 85, and 92 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.
With regard to claim 57, the phrase "for example" (“e.g.” recited in line 5) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 74, which depends from claim 21 recites the limitation "multiple reprogramming factors" in lines 2 and 4. There is insufficient antecedent basis for this limitation in the claim as claim 21 recites “a reprogramming factor”. Appropriate correction is required
Claim 76, which is interpreted as depending from claim 74, is also rejected for incorporating the limitations of a rejected claim while failing to correct the deficiencies.
Claim 76 recites the limitation "The method of claim 75". There is insufficient antecedent basis for this limitation in the claim because Claim 75 is cancelled, thereby rendering Claim 76 incomplete. In light of the specification, the claim limitations, and for the sake of compact prosecution, Claim 76 is being interpreted as being dependent upon claim 74.
Claim 78, which depends from claim 21, recites the limitation "a plurality of constrictions" in line 2. There is insufficient antecedent basis for this limitation in the claim as claim 21 recites a method comprising passing a cell suspension through “a constriction”. Appropriate correction is required.
Claim 85, which depends from claim 78, is also rejected for incorporating the limitations of a rejected claim while failing to correct the deficiencies.
Claim 92, which depends from claims 87 and 21 recites the limitation "the cell suspension" in lines 2 and 3. There is insufficient antecedent basis for this limitation in the claim as claim 21 recites a cell suspension which has not been passed through a constriction. As claimed, claim 92 appears to refer to both a second cell suspension which has already been passed through a constriction and the cell suspension as recited in claim 21. For clarity, the Examiner recommends amending the claim to: “collecting a cell suspension that passed through the constriction and treating the collected cell suspension with the antibiotic.”
Appropriate correction is required.
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.
Claim 126 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more. The claim recites a modified cell which is not markedly different from its naturally occurring counterpart. This judicial exception is not integrated into a practical application because the natural product is not linked to a particular technology. The claims does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional limitations are well-understood, routine and conventional in cell biology.
Applicant is directed to the 2019 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on 1/07/2019, which is found at: https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf; and the October 2019 Update: Subject Matter Eligibility, which is found at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf.
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so, then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so, then does the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
In regard to Step 1, Claim 126 is drawn to a composition of matter-a cell.
In regard to Step 2A Prong one, Claim 126 is drawn to a nature-based product which is not markedly different from its naturally occurring counterpart. Specifically, independent claim 126 is directed to an cell comprising a reprogramming factor wherein the reprogramming factor entered the cell through a perturbation in the cell membrane caused by deformation of the cell due to passage through a constriction. These claims encompass any cell comprising a reprogramming factor, including cells comprising a reprogramming factor that was not delivered to the cell using the instantly claimed method. Thus, this option of the claims is a naturally occurring product. Because instant claims are directed to a nature-based product, i.e., a cell comprising a reprogramming factor, the nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state. Applicant is directed to the publication of Arnold et al. (2011, Sox2+ adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell, 9(4), 317-329) which demonstrates that well before the effective filing date of the instant invention, it was known that Sox2, which is considered to reasonably read on a reprogramming factor, is naturally present in embryonic and adult stem cells (Abstract). Thus, instant claims encompass cells comprising a reprogramming factor that are identical (no difference in structural or functional characteristics) to naturally occurring cells. Furthermore, the fact that instant claim recites a method by which the reprogramming factor is introduced to the cell does not differentiate it from the cells of Arnold et al. because although the claimed cells may be generated by the instantly claimed process, they are identical to what exists in nature (i.e., they comprise the same reprogramming factor). In regard to the process by which the reprogramming factor entered the cell of instant claims, there is no indication in the specification that introducing the reprogramming factor to the cell via the instantly claimed method results in the cells having any characteristics (structural, functional, or otherwise) that are markedly different from the naturally occurring cells in their natural state. In fact, the instant specification discloses that the cells temporarily exhibit perturbations in the cell membrane caused by passage through the constriction and that cells have self-repair mechanisms which allow for the repair of the cell membrane (Para. [0138]) and that these perturbations are “corrected” within the order of about five minutes (Para. [0141]), indicating that there is no permanent structural change to the cell via use of the instantly disclosed method. Because there is no difference between the claimed and naturally occurring cells, the claimed cells do not have markedly different characteristics, and thus are a “product of nature” exception. Accordingly, instant claims are directed to a judicial exception.
In regard to Step 2A Prong two, the judicial exception is not integrated into a practical application. In particular, Claim 126 recites no additional elements to integrate the claimed cell into a practical application. Moreover, Claim 126 recites the single additional element of the process by which the reprogramming factor enters the cell which does not add a meaningful limitation as the process was well known in the art as detailed below (See Sharei), it does nothing to improve a technology, effect a particular treatment, or implement with a particular device to provide a meaningful limitation on the judicial exception.
In regard to Step 2B, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As stated supra, Claim 126 recites no additional elements beyond the cell comprising a reprogramming factor. In regard to the additional element of the method by which the reprogramming factor is introduced, as discussed above with respect to the integration of the natural product into a practical application, the additional element of using a known method to introduce a reprogramming factor does not provide an inventive concept.
Therefore, Claim 126 is directed to a natural cell that is not markedly different from its natural counterpart, is not integrated a practical application, and does not include elements that amount to significantly more than the natural product itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101.
Claim Rejections - 35 USC § 102
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 21-22, 27, 29, 36-37, 42, 50-51, 53, 57-58, 61, 74, 76, 78, 85, and 126 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Sharei et al. (US 2020/0277566 filed 03/13/2020, found in IDS, hereafter “Sharei”).
With regard to claim 21, Sharei discloses a microfluidic system for causing perturbations in a cell membrane comprising a channel having a cell-deforming constriction (Abstract) and a method for delivering a compound into a cell comprising providing a cell suspension which can include a “payload”, passing the cell suspension/payload through a microfluidic channel having a constriction such that the constriction causes perturbations in the cell which allows the payload to pass into the cell (Para. [0020]).
Additionally, Sharei discloses that the disclosed techniques comprise mechanical deformation of the cell as it passes through the constriction (Para [0006], lines 21-22) and that the payload can comprise various compounds or compositions (Para. [0007]) which can be delivered to induce cell reprogramming (Para. [0030], line 16), which is considered to reasonably read on allowing a reprogramming factor to enter the one or more cells thereby inducing reprogramming of the one or more cells (see also Figs 1A and 1B and Example 6).
With regard to claim 22, Sharei discloses that the cells are contacted with the compound/payload to be delivered into the cell during passage through the constriction (Para. [0020]).
With regard to claims 27 and 29, Sharei discloses that material such as siRNA can be co-delivered to a cell (Para. [0026], lines 5-7, [0217]), which is considered to reasonably read on a reprogramming factor comprising a nucleic acid wherein the nucleic acid comprises RNA.
With regard to claims 36 and 37, Sharei discloses use of the method to deliver transcription factors, including SOX2 (Para. [0197], lines 1-3).
With regard to claim 42, Sharei discloses that the method can be used for cell conversion and provides an exemplary embodiment of conversion of fibroblasts to neurons (Para. [0244], lines 1-3) and also discloses wherein the method is used to generate iPSCs, which can be differentiated into neurons (Example 6, and Para. [0243], lines 1-5).
With regard to claims 50 and 51, Sharei discloses that material can be delivered into cells such as embryonic stem cells (Para. [0026], lines 5-7 and Fig. 33)
With regard to claim 53, Sharei discloses that material can be delivered into blood cells (Para. [0030], line 11, Para. [0192], line 8, and Fig. 33).
With regard to claims 57 and 58, Sharei discloses microfluidic device parameters, including the width of the constriction, and provides an embodiment wherein the width is no less than 4 µm (Para. [0008], lines 1 and 5-6).
With regard to claim 61, Sharei discloses that the diameter of the constriction is a function of the diameter of a cell (Abstract) and provides an example wherein the diameter of the constriction is 20% of the diameter of the cell (Para. [0008], line 11)
With regard to claim 74, Sharei discloses use of the method to deliver four transcription factors (Para. [0197], lines 1-2) and that cells can be incubated in a solution containing the payload (i.e., the transcription factors) after passing through the constriction, thereby allowing the payload to enter the cell (Para. [0022], lines 9-12).
With regard to claim 76, Sharei discloses that temporal delivery of reprogramming factors can be optimized including delivery via sequential treatment (Para. [0242], lines 1-2 and 18).
With regard to claim 78, Sharei discloses that multiple constrictions can be placed in parallel or series (Para. [0091], lines 22-23), which is considered to reasonably read on a plurality of constrictions.
With regard to claim 85, Sharei discloses that their method allows for optimization of the delivery of reprogramming factors including optimizing the delivery schedule including treatment frequency (e.g., once every 1, 2, or 3 days) (Para. [0241], lines 3-4 and 14-15) and the temporal delivery of reprogramming factors (Para. [0242], 1-2). Sharei discloses that temporal regulation of reprogramming can be accomplished by delivery of one reprogramming factor (i.e., c-Myc and/or Klf4) initially followed by subsequent addition of a different reprogramming factor (i.e., Nanog) at a later stage (Para. [0242], lines 10-11 and 15-16). As Sharei discloses a method wherein reprogramming factors are delivered via passage of cells through a constriction and these reprogramming factors are delivered sequentially at temporally distinct times, this is considered to reasonably read on wherein cells pass through a first constriction associated with a first reprogramming factor which is delivered to the cell followed by passing through a second constriction associated with a second reprogramming factor which is delivered to the cell.
With regard to claim 126, Sharei discloses production of iPSC cells wherein reprogramming factors are delivered to fibroblasts via use of the disclosed method (See Example 6, Paras. [0224] and [0225], Figs. 35 and 36), which is considered to reasonably read on a cell comprising a reprogramming factor wherein the reprogramming factor entered the cell through a perturbation in the cell membrane generated by deformation of the cell via passage through a constriction.
Claim 126 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Arnold et al. (2011, Sox2+ adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell, 9(4), 317-329).
It is noted that claim 126 includes process steps relating to the introduction of the reprogramming factor, and therefore claim 126 is interpreted as product-by-process. MPEP 2113(I) states:
“Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps… “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” and “The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made…”
In the instant case, claim 126 recites wherein the reprogramming factor enters the cell through a perturbation in the cell membrane which formed due to deformation of the cell as it passes through a constriction, thereby allowing the reprogramming factor to enter the cell. Absent evidence to the contrary, it does not appear that the process by which the reprogramming factor enters the cell impart any structural difference in the cell comprising a reprogramming factor over any other cell which comprises a reprogramming factor.
With regard to claim 126, Arnold et al. discloses that Sox2, which is considered to reasonably read on a reprogramming factor, is a naturally occurring marker of both embryonic and adult stem cells (Abstract). Thus, Arnold et al. discloses a cell comprising a reprogramming factor, Sox2. Absent evidence to the contrary, there appears to be no structural difference between the instantly claimed cell comprising reprogramming factors as generated by the instantly claimed method and the cells comprising a reprogramming factor as disclosed by Arnold et al..
Claim Rejections - 35 USC § 103
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 87 and 92 are rejected under 35 U.S.C. 103 as being unpatentable over Sharei as applied to claim 21 above, and further in view of Chen et al. (WO 2020/180742, filed February 28, 2020, hereafter “Chen”) and Wu et al. (2021, "Microfluidic cell squeezing enables the in vitro generation of induced neurons from human pluripotent stem cells through non-viral transcription factor delivery Applying SQZ(TM) Technology to Regenerative Medicine", found in IDS).
With regard to claim 87, as detailed above and incorporated herein, Sharei teaches microfluidic system for causing perturbations in a cell membrane comprising a channel having a cell-deforming constriction (Abstract) and a method for reprogramming cells comprising passing a cell suspension through a microfluidic device comprising channels having a constriction such that the cell is deformed, thereby causing perturbations in the cell membrane and allowing a “payload” which can include reprogramming factors to enter the cell (Para. [0006], lines 21-22, Para [0020], Figs 1A & 1B, Example 6). Sharei teaches that the payload can comprise DNA molecules (Para. [0007]) and that the method can be used to deliver nucleic acid constructs (Para. [0038], line 10). Additionally, Sharei teaches that the method can also be used to introduce molecules such as a detectable marker (Para. [0027], lines 15-19) for cell screening purposes (Para. [0032], line 1) and wherein the detectable marker can be a fluorescent molecule (Para. [0032], line 7).
While Sharei teaches delivery of nucleic acids, Sharei is silent as to delivery of a nucleic acid encoding an enzyme that confers resistance to an antibiotic.
Chen teaches a method of producing a modified antigen-specific immune cell comprising an exogenous CD 160 protein (claim 15) wherein the method comprises introducing a nucleic acid encoding an exogenous CD 160 protein into a precursor antigen-specific immune cell (claim 22) and that the introduction of the nucleic acid can be performed via transfection (Para. [0015], lines 7-8 and Para. [0060]). Chen further teaches use of a microfluidic system such as CELL SQUEEZE for insertion of proteins into the cell via cellular passage through the microfluidic system (Para. [0107], lines 14-15). It is noted that Applicant’s IDS contains disclosures of Applicant’s related art which also references use of Cell Squeeze (see Wu et al. as found in IDS). Additionally, Chen teaches that nucleic acid sequences can be present in a gene expression cassette (Para. [0147], line 1-2) and that the gene expression cassette can further comprise a selection marker such as an antibiotic resistance gene or reporter gene (Para. [0147], lines 6-9). Further, Chen teaches that selection markers (i.e., reporter genes) can be used to identify transfected cells and that selection markers (i.e., reporter genes) encode polypeptides whose expression is manifested by an easily detectable property such as enzymatic activity (Para. [0175], lines 1-4), for example green fluorescent protein (Para. [0175], line 7). Thus, the antibiotic resistance gene is considered to reasonably read on a nucleic acid encoding an enzyme that confers resistance to antibiotic and the “selection marker” of Chen appears to be analogous to the “detectable marker” as taught by Sharei.
Therefore it would have been obvious to one having ordinary skill in the art to use an antibiotic resistance gene as a detectable/selection marker as taught by Chen in Sharei’s method of reprogramming a cell wherein the method can also be used to deliver a detectable/selection marker with a reasonable expectation of success. As Sharei teaches that detectable/selection markers can be used for cell screening and Chen teaches that detectable/selection markers can be used to identify cells which have been transfected, a skilled artisan would be motivated to use an antibiotic resistance gene in order to be able to reliably screen cells to which intracellular delivery of compounds had been successful via the use of relatively inexpensive methods (i.e., application of antibiotics) and without the need for specialized visual equipment required by fluorescent markers.
With regard to claim 92, the combination of Sharei and Chen is silent as to the steps of collecting the cell suspension which had been contacted with the nucleic acid encoding an enzyme which confers resistance to an antibiotic and treating the cell suspension with the antibiotic. However, the use of a selection marker comprising an antibiotic resistance gene is a technique commonly used in the art which would be well-known to one having ordinary skill in the art. Therefore, a skilled artisan would recognize that the population of cells which had been contacted with the nucleic acid encoding an enzyme which confers resistance to an antibiotic would need to be collected and treated with the antibiotic in order for the nucleic acid encoding an enzyme which confers resistance to an antibiotic to function as a detection marker able to reliably select viable cells. A skilled artisan would recognize that subsequent treatment with the antibiotic would select for only those cells which exhibit resistance to the antibiotic, indicating that the method of introducing the nucleic acid encoding an enzyme conferring resistance to antibiotic was successful for those cells, thereby resulting in a more purified cell population.
Conclusion
No claims are allowed.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631