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 of PCT/US2022/076879 (filed on 9/22/2022), which claims priority benefit of U.S. Provisional Application No. 63/247116 (filed on 9/22/2021) under 35 U.S.C. 119(e).
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 3/11/2024 and 7/09/2025 are in compliance with the provisions of 37 C.F.R. 1.97. All references cited in both IDSs have been fully considered.
However, the listing of references in the specification (par. [0063] and [0071]) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." So unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because of improper labels: each of Figures 1-2, 4, 8-9, and 12 have more than one graph that are placed in two or more pages, some of which are labeled as “Figure 1 (cont.)”, “Figure 2 (cont.)”, “Figure 4 (cont.)”, “Figure 8 (cont.)”, “Figure 9 (cont.)”, or “Figure 12 (cont.)”. According to 37 C.F.R. 1.84(u)(i), “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation “FIG.””. See MPEP § 608.02(V).
In addition to Replacement Sheets containing the corrected drawing figure(s), applicant is required to submit a marked-up copy of each Replacement Sheet including annotations indicating the changes made to the previous version. The marked-up copy must be clearly labeled as “Annotated Sheets” and must be presented in the amendment or remarks section that explains the change(s) to the drawings. See 37 CFR 1.121(d)(1). Failure to timely submit the proposed drawing and marked-up copy will result in the abandonment of the application.
Claim Objections
Claim 1 is objected to because of the following informality: the abbreviation “MMP” is defined to mean Matrix Metalloproteinase but claims 2-14 recite “MMP-9”. To maintain consistency with the rest of the claims, it is recommended that “Matrix Metalloproteinase (MMP)-9” in claim 1 be replaced with “Matrix Metalloproteinase-9 (MMP-9)”.
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.
Claims 1-14 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for treating genotoxicity, does not reasonably provide enablement for inhibiting or preventing development of genotoxicity. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to: (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. See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). But although the analysis and conclusion of a lack of enablement are based on these factors and the evidence as a whole, it is not necessary to discuss each factor in the enablement rejection. See MPEP § 2164.04.
The nature of the invention is a method of administering Matrix Metalloproteinase-9 (MMP-9) to an individual in need thereof. The MMP-9 is defined as being present in an amount that is effective “to inhibit, prevent development of, or treat genotoxicity”.
Genotoxicity, which is characterized by damage to DNA in cells, is known to be caused by radiation, chemotherapy, or toxic chemicals like benzene. The state of the prior art is that radiation, chemotherapy, or toxic chemicals can trigger myelosuppression which results in less red blood cells, white blood cells, and platelets. According to Singh et al. (Expert Opinion on Biological Therapy 2015, Vol. 15, pages 465-471), various biologics have been proposed as radiation countermeasures including: colony-stimulating factor (CSF) like Neupogen that stimulates proliferation, differentiation, and maturation of neutrophils; a truncated derivative of flagellin called Entolimod which is a toll-like receptor 5 (TLR5) agonist that activates NF-[Symbol font/0x6B]B signaling and neutralizes free radicals; and a recombinant human IL-12 cytokine known as HemaMax which is a T cell activator that promotes Th1 maturation (i.e., enhances immunity) and hematopoietic recovery (Table 1, page 467). Other promising radiation countermeasures include myeloid progenitors (Table 2, page 468).
Studies such as Heissig et al. (Cell 2002, Vol. 109, pages 625-637) teach that after myelosuppression, activation of MMP-9 in bone marrow cells releases Kit-ligand, thereby allowing the transfer of endothelial and hematopoietic stem cells from the quiescent to proliferative niche (Abstract, page 625). Heissig et al. thus reveals that MMP-9 promotes hematopoietic regeneration via stem and progenitor cell recruitment. In addition, Walter et al. (Cell Death and Disease 2020, Vol. 11, article # 767, pages 1-14) shows that constitutive expression of MMP-9 in colonic epithelium of mice correlates with reduced levels of reactive oxygen species, decreased DNA damage, and upregulated mismatch repair pathways (Abstract, page 1). This study suggests that MMP-9 expression regulates DNA genomic stability in colitis-associated cancer. However, no prior art could be found that directly teaches preventing or treating genotoxicity through administration of exogenous MMP-9 to a subject. Thus, the nature of the invention is deemed unpredictable.
In working examples, the radiomitigative ability of entolimod in animal models of lethal acute radiation syndrome (ARS) induced by total body irradiation (TBI) was found to be mediated by neutrophils that release MMP-9 (par. [0056]). Applicant then evaluated the effect of administering three different concentrations of MMP-9 on mice 24 hours after TBI (par. [0057]). Results show that MMP-9 increased the production of hematopoietic pluripotent precursors (HPPs) in the bone marrow, with the concentration of 10 µg/kg showing optimal recovery similar to entolimod (Figure 5A). This amount of MMP-9 also improved % survival of irradiated mice similar to the one observed with entolimod (Figure 5B). Moreover, in the absence of neutrophils, HPPs were found to only recover to similar levels observed in mice with neutrophils when both MMP-9 and entolimod were administered (Figure 5C), indicating that the neutrophils’ release of MMP-9 and TLR5 stimulated-inflammatory response are essential for radiomitigation. However, applicant did not conduct experiments in which MMP-9 is administered to the subject prior to TBI. There is thus no evidence demonstrating that administering MMP-9 can block genotoxicity from occurring or progressing.
So even though the disclosure is enabled for treating genotoxicity using MMP-9 as supported by the working examples, it does not support its inhibition or prevention of its development. Given the unpredictability of the invention and insufficient working examples that can demonstrate effectiveness to inhibit or prevent genotoxicity, claiming the use of MMP-9 as broadly recited in the claims is not enabling because, following the guidance presented therein, one cannot practice the claimed method without performing substantial experimentation to prove that administering MMP-9 to a subject would protect the subject from the onset or development of genotoxicity.
The claims are therefore not commensurate in scope with the disclosure.
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.
Claim 7 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 7 recites “to provide a stated effect”. The term “stated effect” is confusing as it cannot be determined what it means. Does it refer to claim 1’s intended effect of inhibiting, preventing development of, or treating genotoxicity? In the interest of compact prosecution, the examiner interprets “stated effect” as referring to said intended effect.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Li (Pub. No. US 2019/0060420 A1).
According to Li, plasminogen is a zymogen synthesized in the liver and cleaved to produce the enzyme plasmin, which can hydrolyze components of the extracellular matrix and activate pro-metalloproteinases to form active metalloproteinases (par. [0003]-[0004]). Li provides a method of using plasminogen or plasmin to treat and/or eliminate radiation damage, chemical damage, and related diseases in a subject. The damage refers to body organ and tissue damage caused by radiotherapy, chemotherapy, or chemoradiotherapy such as damage to a bone marrow hematopoietic system, as well as decrease in general health conditions, systemic side effects, and local side effects caused by radiotherapy, chemotherapy, or chemoradiotherapy (par. [0007]).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHELLE F PAGUIO FRISING whose telephone number is (571)272-6224. The examiner can normally be reached Monday-Friday, 8:00 a.m. - 4:00 p.m..
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie L. Gordon can be reached at (571) 272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Michelle F. Paguio Frising/Primary Examiner, Art Unit 1651
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