DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/26/2026 has been entered.
Response to Amendments
Applicant's amendments filed 5/26/2026 to claims 77, 81-83, 85, and 87 have been entered. Claims 1-68, 84, 86, and 88 are canceled. Claim 89 has been added. Claims 69-83, 85, 87, and 89 remain pending, of which claims 77-83, 85, 87, and 89 are being considered on their merits. Claims 69-76 remain withdrawn from consideration. References not included with this Office action can be found in a prior action.
Applicant is hereby notified that the insertion of new matter into the claims has necessitated the removal of the 35 U.S.C. § 101 rejection of claim 87 and the 35 U.S.C. § 103 rejections over claims 85 and 87. However, removal of new matter will likely result in the reinstatement of those rejections.
Any other rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
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.
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 85, 87, and 89 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for cells capable of treating an infection selected from the group consisting of neutrophils and mesenchymal stem cells, does not reasonably provide enablement for neutrophil-committed progenitor cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 USPQd 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Claim 85 is directed towards a method of making an infection-killing formulation composition, wherein the composition comprises neutrophil-committed progenitor cells in a carrier. Claims 87 and 89 depend from or incorporate the limitations of claim 85.
Before the invention was filed, the prior art as reviewed by Alcayaga-Miranda et al. (Frontiers in Immunology (2017), 8(339), 15 pages) teaches that stem/progenitor cells capable of treating infection was limited to mesenchymal stem cells (Abstract). Alcayaga-Miranda teaches that mesenchymal stem cells produce various species of antimicrobial peptides which interact with molecular targets on the cell surface or within target cells (AMPs; also called “host defense peptides”) (see subheading “Antimicrobial Peptides” on p2-3). Alcayaga-Miranda teaches that the antimicrobial peptides made by mesenchymal stem cells are capable of killing bacterial, fungal, viral, and parasitic pathogens (Table 3), and that the type of AMP varies across different sources of mesenchymal stem cells (Table 4). Drescher and Bai (Virus Research (171(1), 2013, 1-7;) teach that neutrophils are inherently capable of killing bacterial and fungal cells and viruses during infection (see the Abstract and the 1st paragraph of subheading “2. Protective Roles” on p2).
Zhu (Cell Reports (August 2018), 24, 2329-2341; Reference U) teaches unipotent neutrophil progenitor cells (Summary), obtained from bone marrow and which are taught as Ly6G+ Lin- CD117+ and Ly6A/E- (the paragraph spanning both columns of page 2330 and Fig. 1). However, Zhu does not teach that the unipotent neutrophil progenitor cells are capable of directly treating an infection.
Yáñez (Immunity (2017), 47, 890-902 plus appended Supplemental Information; Reference V) teaches granulocyte-monocyte progenitor cells produce a mixed population of granulocytes and monocytes but not dendritic cells in vitro in methylcellulose cultures (page 891, right column, the paragraph starting “Using these gating strategies…” and Fig. S2B). However, Yáñez does not teach that the granulocyte-monocyte progenitor cells are capable of directly treating an infection.
There is no teaching nor suggestion in Alcayaga-Miranda, Drescher and Bai, Zhu, and Yáñez that neutrophil-committed progenitor cells for claim 85 are capable of directly killing any species of infective agent or cells infected by any species of infective agent as required by the claims.
While the prior art is reasonably enabled for neutrophils and mesenchymal stem cells as being capable of directly treating an infection, the prior art is unpredictable towards stem cells that are not mesenchymal stem cells in view of Applicant’s controlling definition of “stem cells” and so more guidance is required to satisfy the enablement requirement. See M.P.E.P. § 2164.03, in that the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.
The working examples of the specification are limited to neutrophils and hematopoietic stem cell-derived neutrophils (see Examples 1-14). However, there is no evidence in the specification nor the prior art that neutrophil-committed progenitor cells are capable of directly killing any species of infective agent or cells infected by any species of infective agent. The plain meaning of “neutrophil-committed progenitor cell” cannot be reasonably held as synonymous for “neutrophil” as a species of terminally differentiated cell type when read in light of the specification (see M.P.E.P. § 2111.01).
Given the unpredictability of the prior art and lack of guidance in the specification, there would be an undue burden on a person skilled in this art to make and use the claimed methods to their full scope. A person skilled in this art would be left to test the generic and unspecified neutrophil-committed progenitor cell(s) operability without any a priori knowledge of operative versus inoperative embodiments and thus rising to the level of undue burden of experimentation. See M.P.E.P. § 2164.08(b).
For the reasons given above, claims 85, 87, and 89 are rejected under 35 U.S.C. § 112(a).
Claims 85, 87, and 89 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.
These are new matter rejections. The proscription against the introduction of new matter in a patent application (35 U.S.C. 132 and 251) serves to prevent an applicant from adding information that goes beyond the subject matter originally filed. See In re Rasmussen, 650 F.2d 1212, 1214, 211 USPQ 323, 326 (CCPA 1981). See MPEP § 2163.06 through § 2163.07 for a more detailed discussion of the written description requirement and its relationship to new matter. The written description requirement prevents an applicant from claiming subject matter that was not adequately described in the specification as filed. New or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (a subgenus is not necessarily described by a genus encompassing it and a species upon which it reads).
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117. Note that a description of individual elements in the specification does not necessarily lead to adequate description of their combination. See Hyatt v. Dudas, 492 F.3d 1365, 1371, 83 USPQ2d 1373, 1376-1377 (Fed. Cir. 2007) and M.P.E.P. § 2163(II)(A).
Regarding claim 85, the original disclosure does not support neutrophil-committed progenitor cells having the functional property of infection killing as claimed. The specification is limited to granulocytes (e.g. [0099] of pre-grant-publication of the instant Application, US2024/0285681). However, disclosure of “neutrophil-committed progenitor” is limited to [0237], which does not teach the combination of “neutrophil-committed progenitor” with the gene expression profile of the claims. Claim 85 as amended does not recite any previously presented original claim limitation as a basis for support, and the drawings make no mention of any neutrophil-committed progenitor cells.
Applicant must either specifically point out the original descriptive support for the full scope of claim 85 to obviate the new matter rejection necessitated by Applicant’s amendment to claim 85, or amend claim 85 accordingly in the next reply to remove the new matter as set forth above.
In so much that claims 87 and 89 depend from or incorporate the limitations of claim 85, these claims must incorporate the new matter of claim 85 and so must also be rejected under 35 U.S.C. § 112(a).
Claims 77-83 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 77 steps (a)-(c) have no relationship to the preamble and step (d), and “capable of differentiating” is not afforded the same plain meaning as an active step of differentiating the claimed stem cells into neutrophils or providing stem cell-derived neutrophils. As such, claim 77 is indefinite as it fails to interrelate essential elements; see M.P.E.P. § 2172.01. The recitation of stem cells and neutrophils in the claim exist in parallel to each other, and the claim is incoherent and vague as if the neutrophils are or are not supposed to be differentiated from the stem cells as both interpretations of the scope of the claim are mutually exclusive. It is further unclear what sources of neutrophils are and are not permitted within the scope of the claim. Applicant appears to understand the plain meaning of differentiating one cell type into another in view of the amendments to claim 85, so it is unclear why claim 77 was not amended accordingly.
If Applicant intended claim 77 to be directed towards a method of differentiating neutrophils from the claimed stem cells, then Applicant might overcome this rejection by adding a first step of differentiating the hematopoietic stem cells or induced pluripotent stem cells into neutrophils needs to claim 77 before step (a), the preamble amended to remove recitation of stem cells, and step (d) deleted to clarify the scope of the claim. If Applicant intended claim 77 to be directed towards hematopoietic stem cell-derived or induced pluripotent stem cell-derived neutrophils, then Applicant might overcome this rejection by removing the recitation of stem cells from the preamble of claim 77 and step (d) deleted combined with replacing “neutrophils” in step (a) with “hematopoietic stem cell-derived or induced pluripotent stem cell-derived neutrophils” to clarify the scope of the claim.
In so much that claims 78-83 depend from claim 77 and do not resolve the point of confusion, these claims must be rejected with claim 77 as indefinite.
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.
Claims 77-81 are rejected under 35 U.S.C. 103 as being unpatentable over in Lázaro-Diez et al. (Scientific Reports (2017), 7:4571, 11 pages) in view of Morishima et al (J. Cell. Physiol. (2010), 226:1283-1291).
In view of the indefiniteness rejections and in the interest of compact prosecution, this rejection addresses the embodiment of induced pluripotent stem cell-derived neutrophils. In view of the 35 U.S.C. § 112(d) rejections above and in the interest of compact prosecution, claims 82 and 83 are rejected with claims 77 and 81.
Lázaro-Diez teaches a method comprising 1) obtaining neutrophils from the whole blood of a human donor (p8, subheading “Neutrophil isolation from whole human blood) 2) mixing and incubating the obtained neutrophils with Acinetobacter sp. in aqueous BHIB broth or LB (p8, subheading “Phagocytosis experiments”), 3) measuring/quantifying the percentage of Acinetobacter sp. killed by the neutrophils indirectly by quantifying neutrophil elastase release, citrullinated histone H3, and extracellular DNA (i.e. NETs) (Fig. 5) thus obtaining a population of neutrophils capable of treating a bacterial infection and reading on claims 77, the embodiment of a bacterium for the infective agent of claims 77, 79, 80, and 87, the wherein clause of step (b) of claim 77, and claims 79 and 80.
Regarding claim 77, Lázaro-Diez does not differentiating any species of stem cell into neutrophils
Morishima teaches a method of differentiating human induced pluripotent stem cells (i.e. hiPSCs) into neutrophils (Abstract, and “Differentiation of iPS cells” on p1284), reading in-part on claims reading on claims 77, 82, 83, 85, and 88 and the embodiment of induced pluripotent stem cells for claims 84, 86, and 88. Morishima teaches that the hiPSC-derived neutrophils would be useful in methods of determining the pathogenesis of various blood diseases and the development of novel therapeutic approaches (p1284, left column, paragraph starting “Recent reports describe…”), reading in-part on claims 77, 82, 83, 85, and 88.
Regarding claim 77 and claims 78-81, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the neutrophils of Lázaro-Diez with the human induced pluripotent stem cell-derived neutrophils of Morishima. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lázaro-Diez and Morishima are directed in-part towards compositions of the same cell, i.e. neutrophils. The skilled artisan would have been motivated to do so because Morishima teaches that the hiPSC-derived neutrophils would be predictably advantageous in methods of determining the pathogenesis of various blood diseases and the development of novel therapeutic approaches, and would also be predictably advantageous as a noninvasive source of neutrophils in the methods of Lázaro-Diez.
Regarding the killing percentage of claims 78 and 81, and the gene expression profile of 81, a whereby/wherein clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited. See M.P.E.P. § 2111.02 and 2111.04. In this case, these wherein clauses are simply the intended result of steps (a)-(d) of claim 77 and which are entirely taught by the combination of Lázaro-Diez and Morishima. Lázaro-Diez and the instant Application are both directed towards in vitro bacterial killing assays and the same cell type, neutrophils differentiated from induced pluripotent stem cells, and so there is a reasonable expectation absent any showing to the contrary that the same or similar steps of Lázaro-Diez would generate the same gene expression profiles as claimed with the hiPSC-derived neutrophils of Morishima. See M.P.E.P. § 2112.01: “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." .
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 82 is rejected under 35 U.S.C. 103 as being unpatentable over Lázaro-Diez in view of Morishima as applied to claim 77 above, and further in view of in view of Lippolis and Reinhardt (Veterinary Immunology and Immunopathology (2005), 103, 53-65).
The teachings of Lázaro-Diez and Morishima are relied upon as set forth above, and read on the gene expression profile and killing percentage for the same rationale set forth for claim 81.
Regarding claim 82, Lázaro-Diez and Morishima does not teach detecting changes in protein product of claim 81 utilizing proteomic techniques.
Lippolis and Reinhardt teach methods of proteomic analysis of mammalian neutrophils, identifying over 250 proteins (Abstract; detailed methods on p54-56), reading on claim 82. Lippolis and Reinhardt teach that reduced neutrophil function in the mammary gland is concomitant with an increased incidence of mastitis and that there is a need in this art to improve understanding of the underlying cause of neutrophil immunosuppression by determining the protein expression profile of neutrophils (1st two paragraphs of the Introduction on p53), reading on claim 82.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to further detect changes in the protein expression profile of the neutrophils of Lázaro-Diez in view of Lippolis and Reinhardt. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lázaro-Diez and Lippolis and Reinhardt are directed towards mammalian neutrophils and because Lippolis and Reinhardt teach detailed methods of proteomic analysis of mammalian neutrophils. The skilled artisan would have been motivated to do so because Lippolis and Reinhardt teach that reduced neutrophil function in the mammary gland is concomitant with an increased incidence of mastitis and that there is a need in this art to improve understanding of the underlying cause of neutrophil immunosuppression by determining the protein expression profile of neutrophils, thereby predictably improving upon the methods of Lázaro-Diez.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 83 is rejected under 35 U.S.C. 103 as being unpatentable over Lázaro-Diez in view of Morishima as applied to claim 77 above, and further in view of in view of Niemiec et al. (BMC Genomics (2017), 18:696, 21 pages).
The teachings of Lázaro-Diez and Morishima are relied upon as set forth above, and read on the gene expression profile and killing percentage for the same rationale set forth for claim 81.
Regarding claim 83, Lázaro-Diez and Morishima does not teach detecting changes in protein product of claim 81 utilizing transcriptomic techniques.
Niemiec teaches methods of analyzing the transcriptome of a population of human neutrophils infected with Candida albicans (Abstract; p16-17, subheading “Infections of neutrophils of NETs with Candida albicans” for detailed methods), reading on claim 82. Niemiec teaches that neutrophils are considered transcriptionally inactive (Abstract), reading on claim 83. Niemiec teaches about 252 genes are induced in neutrophils in response to infection with Candida albicans after about 60 minutes and thus contributing to the understanding of host-pathogen interaction (Fig. 1A; last paragraph of the Background on p2), reading on claim 83.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to further detect changes in the RNA transcript expression profile of the neutrophils of Lázaro-Diez in view of Niemiec. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lázaro-Diez and Niemiec are directed towards human neutrophils infected with a species of microbe and because Niemiec teaches detailed methods of transcriptomic analysis of human neutrophils. The skilled artisan would have been motivated to do so because doing so would be predictably advantageous to contribute to the understanding of host-pathogen interaction between Lázaro-Diez’s human neutrophils and the Acinetobacter sp of Lázaro-Diez.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 7-12 of the reply have been fully considered, but not found persuasive of error for the reasons given below. Applicant’s arguments on pages 8-9 are not found persuasive over the modified grounds of rejection set forth above under 35 U.S.C. § 112(a) and 112(b).
In response to applicant's argument on pages 10-11 of the reply that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., either 1) a first and active method step of differentiating neutrophils from the claimed stem cells, or 2) a first and active method step of providing hematopoietic stem cell-derived or induced pluripotent stem cell-derived neutrophils) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
On page 11 of the reply, Applicants rely on arguments traversing the above rejection of claims 77-81 over Lázaro-Diez in view of Morishima to traverse the rejection of claim 82 further in view of Lippolis and Reinhardt and to traverse the rejection of claim 83 further in view of Niemiec. Therefore, the response set forth above to arguments also applies to this rejection.
In so much that the elected claims are not in condition for allowance, Applicant’s request for rejoinder on page 11 of the reply is not persuasive. Applicant is reminded that in order to be eligible for rejoinder, claims to a nonelected invention must depend from or otherwise require all the limitations of an allowable claim, and that withdrawn claims that do not require all the limitations of an allowable claim will not be rejoined; see M.P.E.P. § 821.04.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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