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 .
Response to Amendments
Applicant's amendments filed 1/23/2026 to claims 77, 81, and 85 have been entered. Claims 1-68 are canceled. Claims 69-88 remain pending, of which claims 77-88 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 Claims 69-76 remain withdrawn from consideration.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.
The instant amendments to claim 77 have overcome the 35 U.S.C. § 102 and 103 rejections of record over Klempner, which are withdrawn. New grounds of rejection are set forth below necessitated by the claim amendments.
Any other rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.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(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 77-88 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 generic stem cells and does not reasonably provide enablement for the narrower embodiment of induced pluripotent stem cells, hematopoietic stem cells, and generic precursor/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.
In view of the indefiniteness rejections above and in the interest of compact prosecution, this rejection addresses the embodiment of cells capable of treating an infection selected from the group consisting of neutrophils and mesenchymal stem cells for claim 77.
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.
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 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; Reference W) 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).
There is no teaching nor suggestion in Alcayaga-Miranda nor Drescher and Bai that any other species of stem cells are capable of directly killing any species of infective agent or cells infected by any species of infective agent as required by claim 77, and there is no evidence that the induced pluripotent stem cells, embryonic stem cells, hematopoietic cells, and generic precursor/progenitor cells of claim 84 are capable of directly killing any species of infective agent or cells infected by any species of infective agent.
While the prior art is reasonably enabled for neutrophils and mesenchymal stem cells, 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 induced pluripotent stem cells, embryonic stem cells, hematopoietic cells, or generic precursor/progenitor cells are capable of directly killing any species of infective agent or cells infected by any species of infective agent.
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 either the generic stem cells of claim 77 or the induced pluripotent stem cells, embryonic stem cells, hematopoietic cells, and generic precursor/progenitor cells of claim 84 for 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 77-88 are rejected under 35 U.S.C. § 112(a).
Claims 77-88 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 has been amended to recite a “stem cell that differentiates into a neutrophil” in the preamble. However, the claim does not recite any step of differentiation and so there are at least two reasonable interpretations to the scope of the claim that cannot be distinguished from each other. Either 1) the claimed stem cells are capable of differentiating into neutrophils, i.e. the claimed method is directed in-part to stem cells, or 2) the claimed stem cells are differentiated into neutrophils, and the product produced by the claimed method is only neutrophils. The confusion stems from the recitation of “differentiates” in the preamble, because steps (a)-(c) of the claim appear to be independent from step (d), and because step (d) occurs after steps (a)-(c) so it is entirely unclear where in the claim the stem cells would be differentiated into neutrophils. If Applicant intended to narrow the scope of claim 77 by adding step(s) of stem cell differentiation into neutrophils, then Applicant would likely overcome this rejection by moving obtaining step (d) and a new step of stem cell differentiation preceding step (a) in the claim. As phrased, it is entirely unclear which cell types (neutrophils or generic stem cells or both) are required to be capable of treating an infection in a subject. Correction is required.
Claims 77 and 85 recite “obtainable”, which blurs the metes and bounds of the claim as it is unclear if the cells of the method claim must be obtained from a donor or not, which is made more confusing as claim 77 is ambiguous to the source of the neutrophils as set forth in the preceding paragraph. “obtainable” raises similar issues of exemplary claim language as set forth in M.P.E.P. § 2173.05(d). Correction is required.
The term “unsuitable” in claim 81 is a relative term which renders the claim indefinite. The term “unsuitable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Clarification and/or correction is required.
Claim 82 depends from claim 81, and recites measuring expression level by proteomic techniques. Claim 83 depends from claim 81, and recites measuring expression level by transcriptome techniques. However, claim 81 is already limited to changes in gene expression and so the metes and bounds of the claims is blurred because the plain meaning of “proteomic” in this context of detecting changes in protein expression and the plain meaning of “transcriptomic” in this context of detecting changes in RNA transcript expression. It is unclear which detection method would be controlling of the scope of claims 82 and 83. Correction is required.
Because claims 78-88 depend from claim 77 and do not resolve the points of confusion, these claims must also be rejected with claim 77 as indefinite.
Claims 82 and 83 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 82 depends from claim 81, and recites measuring expression level by proteomic techniques. Claim 83 depends from claim 81, and recites measuring expression level by transcriptome techniques. The plain meaning of “proteomic” in this context of detecting changes in protein expression and the plain meaning of “transcriptomic” in this context of detecting changes in RNA transcript expression, and claim 81 is already limited to changes in gene expression and so claims 82 and 83 fail to further limit the scope of claim 81.
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 87 and 88 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
In view of the indefiniteness rejections above and in the interest of compact prosecution, this rejection address the embodiment of neutrophils and the product-by-process limitation of stem cells differentiated into neutrophils.
The claims recite a natural product, neutrophils, and product-by-process limitations which incorporate the methods of claims 85 and 77 towards stem cell-derived neutrophils. This judicial exception is not integrated into a practical application because there is no evidence of record and the claims do not require the claimed cells to possess any markedly different characteristic as compared to the nearest natural counterpart. Similarly, the judicial exception is not integrated into a practical application because there is no evidence of record that the product-by-process limitations impart any markedly different characteristic to the claimed cells as compared to the nearest natural counterpart. Neutrophils are inherently capable of killing bacterial cells, see the teachings of Drescher and Bai (Virus Research (171(1), 2013, 1-7), who 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) and so the “infection killing” property of composition claim 87 is an inherent feature of the naturally occurring cells.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because claims are only directed towards a composition comprising neutrophils.
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 77-88 are rejected under 35 U.S.C. 103 as being unpatentable over in Lázaro-Diez et al. (Scientific Reports (2017), 7:4571, 11 pages; Reference U) in view of Morishima et al (J. Cell. Physiol. (2010), 226:1283-1291; Reference V).
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 “Phacocytosis 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, claims 79 and 80, and the embodiment of broth as a carrier for claim 85.
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 preamble of claim 77, the wherein clause of step (d) of claim 77, and claim 78, and the gene expression profile of claims 81-83, 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, 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. 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).
In view of the 35 U.S.C. § 112(d) rejections above and in the interest of compact prosecution, prior art is applied against claim 82.
The teachings of Lázaro-Diez and Morishima are relied upon as set forth above.
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).
In view of the 35 U.S.C. § 112(d) rejections above and in the interest of compact prosecution, prior art is applied against claim 83.
The teachings of Lázaro-Diez and Morishima are relied upon as set forth above.
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 6-11 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
On page 6 of the reply, Applicant alleges that the instant amendments to claim 77 have overcome the scope of enablement rejections of record under 35 U.S.C. § 112(a). This is not found persuasive because the amendments raise substantial issues of claim clarity and construction under 35 U.S.C. § 112(b) such that the claims are construed as being directed towards either stem cells or neutrophils capable of treating an infection such that the scope of enablement remains reasonably applied to the rejected claims.
On pages 6-7 of the reply, Applicant alleges that “unsuitable” is definite with respect to 35 U.S.C. § 112(b). This is not found persuasive because none of Applicant’s arguments what degree of “suitability” is and is not encompassed by the scope of the claims and how a person of ordinary skill in the art would reasonably determine the scope of “unsuitable” as claimed.
On page 7 of the reply, Applicant alleges that “obtainable” is definite with respect to 35 U.S.C. § 112(b). This is not found persuasive of error, because “obtainable” raises similar issues of exemplary claim language as set forth in M.P.E.P. § 2173.05(d), and none of Applicant’s arguments clarify what source of neutrophils are and are not within the scope of the claims.
On page 7-8 of the reply, Applicant alleges that claims 82 and 83 satisfy 35 U.S.C. § 112(d). This is not found persuasive because Applicant the plain meaning of “gene” is limited to DNA sequences and so necessarily measurement of gene expression by the measurement of DNA expression. Applicant has not presented any evidence that would otherwise redefine and broaden the plain meaning of “gene” to include amino acid sequence(s) encompassed by the proteomic methods of claim 82, or the RNA sequence(s) encompassed by the transcriptomic methods of claim 83.
Notwithstanding the 35 U.S.C. § 112(b) rejections of record, Applicant’s arguments on page 8 of the reply regarding the 35 U.S.C. § 101 rejection of record are not found persuasive of error because there is no evidence of record that the nature-based products in the claim, i.e. neutrophils, have any markedly different characteristics from its naturally occurring counterpart. See M.P.E.P. § 2106.04(c)(I)(B).
Applicant’s remaining arguments on pages 8-11 of the reply are not found persuasive over the new grounds of rejection set forth above under 35 U.S.C. § 103 and necessitated by the instant claim amendments.
Conclusion
No claims are allowed. No claims are free of the art.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at 571-272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Sean C. Barron/Primary Examiner, Art Unit 1653