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 15-25 are pending and under examination.
Claim Rejections - 35 USC § 112 – Indefiniteness
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.
Claims 17 and 22-25 are rejected under 35 U.S.C. 112(b) as failing to set forth the subject matter which the inventor or a joint inventor regards as the invention.
Claim 17 recites that “the SURF4 inhibitor is a culture product of cells genetically engineered to express the SURF4 inhibitor.” The phrase “culture product” is indefinite because it is unclear what product is being claimed. The term may encompass genetically engineered cells themselves, conditioned medium, culture supernatant, viral particles, exosomes, secreted proteins, nucleic acid-containing particles, cellular lysates, or other products derived from cell culture. The claim does not identify the composition, structure, or required components of the “culture product,” nor does it specify whether the product is the engineered cell, a secreted product, a viral vector-containing product, or some other material. Accordingly, one of ordinary skill in the art would not be reasonably apprised of the scope of claim 17.
Claim 22 depends from method claim 15, but recites an anticancer agent without clearly reciting an active method step involving that agent. The claim does not clearly state whether the anticancer agent is administered to the subject, co-administered with the SURF4 inhibitor, administered before or after the SURF4 inhibitor, included in the same pharmaceutical composition, separately formulated, merely contacted with cancer cells, or simply present as an intended additional component. Because claim 22 does not affirmatively recite what is done with the anticancer agent in the claimed method, the scope of the method is unclear. One of ordinary skill in the art would not be reasonably apprised whether infringement requires administration of the anticancer agent, co-formulation with the SURF4 inhibitor, sequential dosing, in vitro contact, or some other act. Claims 23-25, dependent from claim 22, do not remedy the indefiniteness issue.
Claim Rejections - 35 USC § 112 – Written Description
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 15-25 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
The written description requirement is separate from enablement and requires the specification to reasonably convey to those skilled in the art that the inventor had possession of the claimed invention as of the filing date. See MPEP § 2163; Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351-52 (Fed. Cir. 2010). For a claimed genus, the specification must disclose either a representative number of species falling within the genus or structural features common to the genus sufficient for one of ordinary skill in the art to visualize or recognize the members of the genus. Ariad, 598 F.3d at 1350. A claim to a broad functional genus is not adequately described merely by disclosing a desired result or function. Id. at 1349-52.
Claim 15 recites a method of preventing or treating blood cancer by administering an effective amount of a SURF4 inhibitor. The claim is not limited to leukemia, the commercial SURF4 shRNA plasmid used in the examples, any specific nucleic acid sequence, inhibitor structure, inhibitor class, binding site, mechanism of SURF4 inhibition, route of administration, dosage, or particular blood cancer. Thus, claim 15 broadly encompasses use of any SURF4 inhibitor, including shRNA, siRNA, miRNA, antisense molecules, small molecules, compounds, peptides, polypeptides, antibodies, aptamers, protein inhibitors, culture products, gene-editing reagents, and other unidentified SURF4-inhibiting agents, for either treatment of existing blood cancer or prevention of blood cancer.
The specification reasonably conveys possession, at most, of limited embodiments involving SURF4 shRNA-mediated knockdown using the identified commercial SURF4 shRNA plasmid in selected leukemia models. The specification states generally that the SURF4 inhibitor may be selected from a polypeptide, polynucleotide, or compound, and more specifically may be shRNA, siRNA, or miRNA. See specification ¶¶ [0010]-[0012]. However, these passages merely list broad categories of possible inhibitors and do not provide representative species or common structural features for the genus of SURF4 inhibitors. The working examples are directed principally to use of a SURF4 shRNA plasmid identified as Santa Cruz Biotechnology Inc., Cat. No. sc-92607-SH, introduced into 293T cells to generate a lentivirus-containing culture solution used to transfect leukemia cell lines. See ¶ [00111]. Subsequent examples likewise rely on SURF4 shRNA-transfected THP1, HL60, K562, and related leukemia model systems. See ¶¶ [00109]-[00118], [00119]-[00130], [00131]-[00151].
Disclosure of one SURF4 shRNA knockdown approach does not demonstrate possession of the much broader genus of any SURF4 inhibitor. RNAi molecules inhibit gene expression through sequence-specific nucleic acid mechanisms and are not representative of structurally and mechanistically distinct inhibitor classes, such as small molecules, antibodies, peptides, aptamers, protein inhibitors, or compounds that inhibit SURF4 activity without reducing SURF4 mRNA expression. The specification does not disclose structures, chemical formulas, pharmacophores, epitopes, binding domains, consensus motifs, screening hits, or other identifying characteristics sufficient to show possession of these non-shRNA and non-RNAi SURF4 inhibitor classes. The specification also does not reasonably convey possession of preventing blood cancer, because it does not identify at-risk subjects, prophylactic dosing, prophylactic timing, or data showing reduced incidence or delayed onset of any blood cancer.
Claim 16 recites that the SURF4 inhibitor is selected from shRNA, siRNA, and miRNA. Although the specification identifies a commercial SURF4 shRNA plasmid, it does not disclose representative siRNA or miRNA species, nucleotide sequences, target regions, sequence-selection rules, or structural characteristics sufficient to show possession of the full RNAi genus recited. The general statement that the inhibitor may be shRNA, siRNA, or miRNA does not demonstrate possession of all SURF4-targeting shRNA, siRNA, and miRNA embodiments.
Claim 17 recites that the SURF4 inhibitor is a culture product of cells genetically engineered to express the SURF4 inhibitor. The specification describes, at most, a lentivirus-containing culture solution produced from 293T cells transfected with the identified SURF4 shRNA plasmid. See ¶ [00111]. The specification does not reasonably convey possession of the broader genus of culture products from genetically engineered cells that express SURF4 inhibitors, including undefined culture products, cellular products, viral products, secreted products, or other engineered-cell-derived products suitable for therapeutic or prophylactic administration.
Claims 18-20 recite functional biological effects of the SURF4 inhibitor, including increasing reactive oxygen species, increasing pSTAT6 expression, increasing pJNK expression, and decreasing pERK and pAKT expression. The specification reports selected mechanistic effects in limited leukemia cell models using the SURF4 shRNA approach. See ¶¶ [00113]-[00118], [00135]-[00137], [00143]-[00151]. However, the claims are not limited to the tested shRNA, tested leukemia cell lines, or tested conditions. The specification does not show possession of the full genus of SURF4 inhibitors that would produce these functional effects across blood cancer cells generally or in subjects.
Claim 21 recites numerous blood cancers, including AML, CML, B-ALL, T-ALL, CLL, multiple myeloma, myelodysplastic syndrome, myeloproliferative neoplasms, Richter syndrome, hairy cell leukemia, BPDCN, non-Hodgkin’s lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, Hodgkin’s lymphoma, systemic mastocytosis, and Burkitt lymphoma. The specification provides experimental data primarily in selected leukemia models, including THP1, HL60, K562, and mouse leukemia contexts. See ¶¶ [00109]-[00118], [00138]-[00147]. The specification does not provide representative disease-specific examples or rationale sufficient to show possession of treating or preventing the full listed genus of hematologic malignancies using the full genus of SURF4 inhibitors. A listing of blood cancer types at ¶ [0025] does not, by itself, demonstrate possession of methods of treating or preventing each listed cancer using any SURF4 inhibitor.
Claims 22-25 further recite combination therapy and downstream effects involving anticancer agents. Claim 22 broadly recites an anticancer agent, while the specification provides working examples only for selected experiments involving paclitaxel and tunicamycin in SURF4 shRNA-transfected leukemia cells. See ¶¶ [00119]-[00130]. The specification does not disclose a representative number of anticancer agents or class-wide characteristics sufficient to show possession of combining any anticancer agent with any SURF4 inhibitor for preventing or treating blood cancer. Claim 23 is limited to paclitaxel and tunicamycin, but still depends from the unsupported broad method of claim 15 and is not limited to the disclosed shRNA/leukemia-cell embodiments. Claim 24 recites increased expression of “apoptosis-related proteins,” while the specification identifies selected markers such as cleaved caspase 9, cleaved caspase 3, and PARP in limited paclitaxel/shRNA contexts. See ¶¶ [0041]-[0042], [00122]-[00123]. Claim 25 recites increased expression of “ER stress-related genes,” while the specification identifies selected markers such as PERK, phospho-eIF2α, eIF2α, ATF4, and CHOP in limited tunicamycin/shRNA contexts. See ¶¶ [0042], [00128]-[00129]. These limited disclosures do not demonstrate possession of the broad functional genera recited in claims 24 and 25 across all SURF4 inhibitors, all relevant blood cancers, and all combination-treatment contexts.
Accordingly, the specification reasonably conveys possession, at most, of limited embodiments involving SURF4 shRNA-mediated knockdown using the identified commercial SURF4 shRNA plasmid in selected leukemia models, including selected paclitaxel and tunicamycin experimental contexts. The specification does not reasonably convey possession of the broader claimed methods of preventing or treating blood cancer using any SURF4 inhibitor, the full RNAi genus of claim 16, the culture-product genus of claim 17, the functional-result limitations of claims 18-20 and 24-25, the broad blood-cancer genus of claim 21, or the broad anticancer-agent combination of claim 22. Therefore, claims 15-25 fail to satisfy the written description requirement of 35 U.S.C. § 112(a).
Claim Rejections - 35 USC § 112 – Scope of Enablement
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 15-25 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for treating leukemia via SURF4 shRNA-mediated knockdown using the commercial SURF4 shRNA plasmid identified, does not reasonably provide enablement for preventing or treating and blood cancer using any SURF4 inhibitor as claimed. 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.
The enablement requirement requires the specification to teach one of ordinary skill in the art how to make and use the full scope of the claimed invention without undue experimentation. See MPEP § 2164; In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Factors relevant to undue experimentation include the breadth of the claims, nature of the invention, state of the prior art, level of skill in the art, predictability or unpredictability of the art, amount of direction provided, presence or absence of working examples, and quantity of experimentation required. Id. The specification must enable the full scope of the claimed invention, not merely a subset of embodiments. See Amgen Inc. v. Sanofi, 598 U.S. 594, 610-12 (2023).
Breadth and Nature of the Claims
Independent claim 15 broadly recites a method of preventing or treating blood cancer by administering an effective amount of a SURF4 inhibitor. The claim is not limited to leukemia, the identified commercial SURF4 shRNA plasmid, shRNA-mediated knockdown, any particular nucleic acid sequence, any particular inhibitor class, any particular mechanism of SURF4 inhibition, any particular blood cancer subtype, or any prophylactic or therapeutic dosing regimen. Thus, claim 15 encompasses prevention or treatment of any blood cancer using any SURF4 inhibitor, including shRNA, siRNA, miRNA, antisense molecules, small molecules, compounds, peptides, polypeptides, antibodies, aptamers, culture products, gene-editing reagents, and other unidentified SURF4-inhibiting agents. This breadth weighs against enablement.
Guidance and Working Examples
The specification appears enabling, at most, for treating leukemia using SURF4 shRNA-mediated knockdown with the identified commercial SURF4 shRNA plasmid. The working examples are limited to SURF4 shRNA-mediated knockdown in selected leukemia model systems, particularly THP1, HL60, and K562 cells, using the commercial SURF4 shRNA plasmid identified as Santa Cruz Biotechnology Inc., Cat. No. sc-92607-SH. See specification ¶¶ [00109]-[00118]. The specification further describes limited assays measuring apoptosis, cell number, pJNK, pERK, pAKT, ROS, pSTAT6, and related markers in these shRNA-transfected leukemia models. See ¶¶ [00113]-[00118], [00135]-[00151]. The specification also describes selected combination experiments using paclitaxel and tunicamycin in SURF4 shRNA-transfected leukemia cells. See ¶¶ [00119]-[00130]. The animal experiment described at ¶¶ [00138]-[00141] involves subcutaneous injection into NOD-SCID mice of HL60 cells already transfected with SURF4 shRNA before implantation.
These disclosures do not teach how to use non-shRNA SURF4 inhibitors, different RNAi species, or other inhibitor classes to prevent or treat blood cancer across the full claim scope. The specification also does not enable the prevention aspect of claim 15 because it does not identify at-risk subjects, prophylactic dosing, timing, duration, patient-selection criteria, data showing reduced incidence or delayed onset of blood cancer, or any animal model demonstrating prevention of spontaneous, induced, or genetically predisposed hematologic malignancy. The disclosed growth/apoptosis assays and pre-transfected-cell xenograft experiment are directed to activity against existing leukemia cells, not prevention of blood cancer onset.
State of the Art and Predictability
The state of the art supports that the full claim scope would require undue experimentation.
Kim et al. (“SURF4 has oncogenic potential in NIH3T3 cells,” Biochemical and Biophysical Research Communications, Volume 502, Issue 1, 2018, Pages 43-47) teaches that SURF4 is amplified or highly expressed in several cancers, including lymphoma and myeloma, and that SURF4 overexpression promotes oncogenic phenotypes. See Kim, Abstract; § 3.1 and Fig. 1A-1C; § 3.2 and Figs. 2-3. However, Kim does not teach that any SURF4 inhibitor treats or prevents blood cancer, and Kim states that the molecular mechanisms underlying aberrant SURF4 deregulation in cancer require further elucidation. See Kim, Discussion following Fig. 3. Thus, Kim supports that SURF4 may be cancer-associated, but does not make therapeutic or prophylactic SURF4 inhibition across blood cancers predictable.
Das et al. (“RNA Interference-Based Cancer Drugs: The Roadblocks, and the "Delivery" of the Promise,” Nucleic Acid Ther., 2019 Apr;29(2):61-66., Epub 2018 Dec 18) supports that developing effective RNAi-based cancer therapeutics is target-, tumor-, and patient-context dependent. Das explains that, despite promising preclinical data, “we lack advanced clinical data from human cancer patients harnessing RNAi mediated gene silencing,” and identifies the “complexity of cancers as disease targets” as a barrier to RNAi therapeutic development. See Das, p. 61. Das further explains that cancer-cell proliferation can dilute siRNA and affect the duration of gene silencing, such that dosing and therapeutic efficacy depend on the growth kinetics of the particular cancer cells being treated. See Das, p. 62, “Dosing of therapeutics.” Das also states that future RNAi cancer trials require a focused approach, including preselecting patients with genetic signatures predictive of therapeutic response. See Das, p. 64, “Conclusions.” These teachings support that identifying an effective RNAi inhibitor and translating it into a cancer therapy is not predictable merely from identifying a gene as cancer-associated.
Luo et al. (“Advances in RNA therapeutics and its delivery strategies against Multiple Myeloma. J Control Release,” 2025 Sep 10;385:114048, Epub 2025 Jul 1) further supports unpredictability in the blood-cancer RNA therapeutic field. Luo states that although RNA therapeutics show promise against multiple myeloma, “valid nucleic acid targets and favored delivery systems” remain unresolved. See Luo, Abstract. Luo also explains that RNA dysregulation in multiple myeloma involves multilayered regulatory axes and that “a comprehensive understanding of MM-related RNA networks remains elusive.” See Luo, § 2. Luo further states that although many highly expressed target molecules in multiple myeloma cells have been discovered for RNA-based therapies, additional work is needed to optimize efficacy and safety and to determine whether such therapies should be used in combination with current standards of care. See Luo, § 2.3. These teachings show that even within one blood cancer subtype, identification of a molecular target does not predict that inhibition of that target will be therapeutically effective across disease contexts.
These teachings show that developing effective SURF4 inhibitors for blood-cancer treatment or prevention would not have been predictable from the specification’s limited shRNA examples.
Quantity of Experimentation Required
Practicing the full scope of claim 15 would require more than routine experimentation. A person of ordinary skill would need to identify which classes of SURF4 inhibitors are operative, determine whether non-shRNA inhibitors inhibit SURF4 in blood cancer cells, design and validate additional shRNA/siRNA/miRNA species, determine whether SURF4 inhibition produces anti-cancer activity in each relevant blood cancer type, evaluate whether mRNA knockdown correlates with protein reduction and anti-cancer effect, determine whether the inhibitor is effective in a subject, and separately determine whether prophylactic administration prevents or delays blood cancer onset in at-risk subjects. This amount of experimentation would be extensive and unpredictable.
Dependent Claims
Claim 16 is not enabled across its full scope because, although the specification identifies a commercial SURF4 shRNA plasmid, it does not provide representative siRNA or miRNA sequences, validated target regions, activity data, or guidance sufficient to make and use the full genus of shRNA, siRNA, and miRNA SURF4 inhibitors for preventing or treating blood cancer.
Claim 17 is not enabled because the specification describes, at most, a lentivirus-containing culture solution produced using cells transfected with a SURF4 shRNA plasmid. The specification does not teach how to make or use the broad genus of “culture product[s] of cells genetically engineered to express the SURF4 inhibitor” for preventing or treating blood cancer, and does not define the operative product, composition, potency, dose, prophylactic use, or therapeutic use across the full claim scope.
Claims 18-20 are not enabled because the recited functional effects—ROS increase, pSTAT6 increase, pJNK increase, and pERK/pAKT decrease—are demonstrated only in limited SURF4 shRNA-transfected leukemia-cell contexts. The specification does not teach that all SURF4 inhibitors, or even all RNAi inhibitors against SURF4, will produce these effects in blood cancer cells generally or in subjects, nor that these effects are sufficient to prevent blood cancer onset.
Claim 21 is not enabled across the full recited blood-cancer genus. The specification provides experimental evidence primarily for selected leukemia models, while claim 21 extends to numerous biologically distinct hematologic malignancies, including B-ALL, T-ALL, CLL, multiple myeloma, MDS, MPN, Richter syndrome, hairy cell leukemia, BPDCN, non-Hodgkin’s lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, Hodgkin’s lymphoma, systemic mastocytosis, and Burkitt lymphoma. The specification does not provide disease-specific examples or guidance sufficient to establish that SURF4 inhibition would be effective across this full scope, nor any prophylactic model or guidance showing prevention of any of these blood cancers.
Claims 22-25 are not enabled across their full scope. Claim 22 broadly recites an anticancer agent, while the specification provides working examples only for paclitaxel and tunicamycin in selected SURF4 shRNA-transfected leukemia cells. The specification does not teach how to determine which anticancer agents will be effective with which SURF4 inhibitors across blood cancers or in prophylactic settings. Claims 24 and 25 recite broad downstream effects involving “apoptosis-related proteins” and “endoplasmic reticulum stress-related genes,” but the examples show only selected markers under limited experimental conditions.
Conclusion
Accordingly, the scope enabled by the specification is limited to treating leukemia using SURF4 shRNA-mediated knockdown with the identified commercial SURF4 shRNA plasmid, including related assays in selected leukemia model systems and the pre-transfected HL60 xenograft experiment. The specification does not enable the broader claimed methods of preventing or treating blood cancer using any SURF4 inhibitor, nor the full scope of the RNAi, culture-product, functional-result, broad blood-cancer, and combination-therapy limitations of claims 15-25. Practicing the full claim scope would require undue experimentation. Therefore, claims 15-25 fail to satisfy the enablement requirement of 35 U.S.C. § 112(a).
Prior Art Search / Closest Prior Art
The closest prior art identified is Kim et al., “SURF4 has oncogenic potential in NIH3T3 cells,” BBRC (2018). Kim teaches that SURF4 is amplified or highly expressed in several cancers, including lymphoma and myeloma, that high SURF4 expression correlates with poorer survival in lymphoma patients, and that SURF4 overexpression promotes oncogenic phenotypes. Kim also reports that SURF4 siRNA knockdown reduced growth of 293T cells.
Kim, however, does not teach or fairly suggest administering an effective amount of a SURF4 inhibitor to a subject to prevent or treat blood cancer. Kim’s siRNA data are limited to in vitro knockdown and do not teach in vivo administration of a SURF4 siRNA or any other SURF4 inhibitor. Kim does not disclose dosing, route of administration, formulation, biodistribution, safety, or therapeutic efficacy of a SURF4 inhibitor in a subject. Kim’s lymphoma and myeloma disclosures are expression/prognostic correlations, not treatment studies, and do not establish that SURF4 inhibition would prevent or treat blood cancer in vivo.
Applicant’s specification contains leukemia-specific functional data not present in Kim, including SURF4 shRNA-mediated knockdown in THP1, HL60, and K562 leukemia cells, reduced cell number, increased apoptosis, altered signaling markers, increased ROS, selected paclitaxel/tunicamycin combination effects, and a mouse xenograft experiment involving HL60 cells pre-transfected with SURF4 shRNA before implantation.
Accordingly, Kim identifies SURF4 as a cancer-associated gene and potential research target, but does not provide the requisite teaching or reasonable expectation of success for therapeutic or prophylactic administration of a SURF4 inhibitor as claimed. Kim also does not teach the claimed downstream functional effects or combination embodiments.
Conclusion
No claims are allowed.
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/CHRISTOPHER M BABIC/ Supervisory Patent Examiner, Art Unit 1633
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