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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 10/01/2025 is acknowledged. Applicant’s election of species of TNF inhibitor which is a non-antibody peptide in the reply filed on 10/01/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Drawings
The drawings are objected to because: Fig. 1C cuts off “Donor” from the X-axis legend; The two types of lines in Fig. 16C and 27B are indistinguishable. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
It is noted that Fig. 9D is truncated and Applicant may wish to correct this but are not required to.
Specification
Abstract
The abstract of the disclosure is objected to because of the following minor informality: The last sentence recites “is a method of a method of”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Specification
The disclosure is objected to because of the following informalities: TNFa appears occasionally instead of TNFα. Either TNFα should be used exclusively or the first occurrence of TNFa should be explicitly equated to TNFα (e.g., [0020]). Also, in line 4 of [0020], “mTFNa” should be “mTNFα”. In line 4 of [1035], “whil” should be “while”. Paragraphs [0173]-[0176] recite references numbers for which there are no references.
Appropriate correction is required.
The use of the term “PhosFlow” (e.g., [0017]), “Matrigel” (e.g., [0138]), Alexa Fluor, Graphpad ([0170]), each of which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
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.
Claim 2 is 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 2 recites terms of overlapping scope, making the claim metes and bounds unclear. A peptide is defined in [0051] of the specification as synonymous with “antibody”. Also “immunotherapy” encompasses antibodies. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 9 is indefinite because it recites one or more TNF inhibitors is administered with a therapy for treating neuroblastoma. However, according to the claims, TNF inhibitors are themselves a therapy, which makes the wording of claim 9 confusing. Assuming that “a therapy” in the claim refers to a further or additional therapy, indicating this would clarify the claim.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-4, 7 and 9 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 a method of ameliorating neuroblastoma (NB) by administration of a TNFα or TNFR2 inhibitor, does not reasonably provide enablement for prevention of NB, inhibition of only TNFR1 or wherein the inhibitor is a nucleic acid or derivative thereof. 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 three issues of enablement for the instant claims. The first is the result of the breadth of the term “treating”, which includes prevention and prophylaxis. The second is with the use of nucleic acids or nucleic acid derivatives to accomplish the method. The last is with the target of TNF inhibition.
The claims are drawn to a method for treating neuroblastoma in and individual. The specification defines “treating” as including prophylaxis and preventing occurrence of disease ([0048]). This is compatible with the use of the term “individual” including a patient at risk for having a disease ([0049]). However, in order to be able to prevent a disease such as NB, one must first be able to anticipate its onset and second be able to maintain administration throughout the duration of susceptibility so it does not occur. The term “preventing” generally carries the meaning of keeping something from happening. There is no guidance for or working example of anticipating neuroblastoma, nor how to maintain treatment for the necessary duration to prevent the eventual onset of NB.
The included therapeutic agents include a nucleic acid or derivative thereof. The specification discusses use of altering gene or expression activity by a nucleic acid agent, such a guide RNA with CRIPSR/Cas or DNA- or RNA-targeting molecule, including a DNA-binding nucleic acid or proteins which target DNA, such as zinc finger, or transcription activator-like protein (TAL) ([0097]-[0120]). While in vitro CRISPR/Cas9 gene editing has been successfully used in vitro (e.g., Example 4), this is not the case for clinical use. As reviewed by Liu et al. (Precision Clin. Med. 4(3):179-191, 2021, p 182, col. 1, first paragraph), ex vivo CRISPR-Cas gene editing has three potential gene editing applications, none of which encompass reducing expression of or changing TNF or its receptors. Liu et al. state the main in vivo application is to treat monogenic genetic disorders, of which neuroblastoma is not one (p. 182, col. 2, third paragraph). Unresolved issues relate to gene editing efficiency, delivery methods, off-target effects and immunogenicity (e.g., Fig. 4). Other forms of gene therapy are reviewed by High et al. (N. Eng. J. Med. 381(5):455-555, 2019, p. 455, first paragraph), where it is discussed that only six gene therapies have been approved: two chimeric antigen receptor T-cell products for B-cell cancers and four for serious monogenic disorders, the specification does not disclose a chimeric antigen receptor inhibiting TNF or a receptor thereof, nor is NB considered a monogenic disorder. There is no guidance, direction, working example or support in the prior art for treating NB using a nucleic acid or derivative thereof, especially none with a reasonable expectation of success.
The specification examined the roles of TNFα receptors in neuroblastoma. Example 5 ([0135]) shows in Fig. 4A through in vitro TNFR1 and TNFR2 knockout of NB cells with monocyte co-culture that “TNFR2 is critical for monocyte activation”. Example 6 ([0133] and Fig. 5B) shows membrane-bound TNFα (mTNFα) on monocytes is critical for monocyte activation. Example 14 showed that neutralizing antibodies to TNFα, TNFR1 and TNFR2 all reduced IL-6 levels, but only TNFα neutralization reduced IkBa degradation in both monocytes and NB (Fig. 24A-24B). Example 7 showed that TNFα-blocking antibodies decreased IL-6 production and decreased NF-κB signaling as shown through increase in IκBα levels in both NB cells and monocytes ([0134], Figs. 6A-6C). In Example 13 it is stated ([0146]), “These findings demonstrate that NB TNFR2 is crucial for induction of IL-6 production in monocytes, consistent with the observation that mTNFα mediates this induction on the monocytic side.” Even though separate results suggest soluble (s)TNF activates NF-κB signaling in NB cells through TNFR1 ([0147]), it is unclear if based on this that TNFR1 inhibition alone would be sufficient for treatment of NB in a subject. This is supported by Golliot et al. (Canc. Res., 52(11): 3194-200, 1992) which showed in vitro that using an anti-TNFR1 and an anti-TNFR2 antibodies applied to two different NB cell lines, the anti-TNFR1 (A, UTR1) antibody had no effect on SKNFI cells and only 50% inhibition of [3H]thymadine incorporation on SKNBE cells, whereas the anti-TNFR2 (B, HTR5) produced approximately 60% and 90% inhibition, respectively (Fig. 4 and p. 3195, col. 2, last paragraph). The preponderance of evidence suggests that inhibition of TNFR2 is critical, which may be accomplished through inhibition of TNFα, which could inhibit signaling through both receptors. It does not support a reasonable expectation of treatment of NB as claimed through inhibition of TNFR1 alone commensurate in scope with the claims.
Claims 1-4, 7 and 9-11 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.
The claims require administration of a therapeutically effective amount of one or more TNF inhibitors to an individual for treatment of neuroblastoma (NB). There is insufficient support in the specification for the genus of inhibitors which are i) nucleic acids or nucleic acid derivatives, ii) small molecules or iii) immunotherapies, cell therapies and/or antibodies which do not directly bind and antagonize or neutralize TNFα, TNFR1 or TNFR2. The Written Description Guidelines for Examination of Patent Applications (MPEP § 2163) indicates, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice…, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus…." [See MPEP § 2163(II)(A)(3)(a)(ii)] Further, “An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004)” (MPEP § 2163(II)(A)(3)(a)) The function of being a “TNF inhibitor” does not place any structural and/or chemical limitations on the agent. While nucleic acids or derivatives thereof and small molecules do have very broad structural limitations, with each drawn to an extremely large class of molecules, the specification does not support the breadth of these genuses for TNF inhibitors.
Liu et al. (Precision Clin. Med., 4(3):179–191, 2021) is a post-filing reference that reviews CRISPR-Cas gene-editing for disease treatment, which is the method used in the instant application to make the NB TNFR knock out (KO) cells. However, the actual in vivo use is not routine or well-known and is referred to only as having “promise” and “potential” (e.g., Abstract of Liu et al.). Ex vivo CRISPR-Cas gene editing has three potential gene editing applications (p 182, col. 1, first paragraph), none of which encompass reducing expression of or changing TNF or its receptors. Liu et al. states (p. 182, col. 2, third paragraph) the main in vivo application is to treat monogenic genetic disorders, of which neuroblastoma is not one. Unresolved issues relate to gene editing efficiency, delivery methods, off-target effects and immunogenicity (e.g., Fig. 4 of Liu et al.). The only use of nucleic acids in the instant specification was as part of a CRISPR/cas9 system used to knock out TNFα, TNFR1 or TNFR2 in NB cells (e.g., [0161]). Other forms of gene therapy are reviewed by High et al. (N. Eng. J. Med. 381(5):455-555, 2019, p. 455, first paragraph), where it is discussed that only six gene therapies have been approved: two chimeric antigen receptor T-cell products for B-cell cancers and four for serious monogenic disorders. These types of gene therapies are not suitable for treatment of neuroblastoma in which suppression of the activity of TNFα with its receptors is the goal. As a result of the teachings or lack thereof in the art and in the specification, the method does not have written description for wherein the TNF inhibitor is a nucleic acid, nucleic acid derivative, or direct nucleic acid effector.
There are no small molecule TNF inhibitors disclosed in the specification. According to the prior art, O’Connell et al. (Nat. Comm. 10:5795, 12 pages, 2019, Abstract) states, “While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products.” In contrast (p. 2, first paragraph), “Biologics such as infliximab, etanercept, adalimumab, golimumab and certolizumab pegol have proved efficacious in the clinic and have a well-documented mode of action and side-effect profile1.” While O’Connell et al. identified a new TNF antagonist class of small molecules that shows ability to inhibit TNF in a TNF-dependent mouse model using exogenously injected TNF, and therapeutic efficacy in a collagen antibody-induced arthritis mouse model (150mg/kg twice daily, p. 7, col. 1, first paragraph), these small molecules have not been further tested. O’Connell does not discuss treatment of a cancer. The authors conclude, “Here we demonstrate that fragment-based drug discovery can be used to provide starting points for orally active compounds that modulate protein-protein interactions.” There is insufficient description of a small molecule for use in the claimed method to support written description for the genus of agent which are small molecules.
An immunotherapy is also broadly defined in the specification as including etanercept therapy (a Fc:TNFR2 fusion protein), antibody therapy, adoptive cell therapies such as chimeric antigen receptor-expressing T or NK cells ([0176]). There is no teaching in the instant specification or prior art of using adoptive or other cell therapy targeting TNF or a receptor thereof used in patients. Aside from the use of etanercept to treat some autoimmune diseases, the closest immunotherapy in the prior art is using a TNF inhibitor in conjunction with an immune checkpoint blocker (ICB) as discussed by Montfort (J. ImmunoTher. Canc. 7:303, 4 pages, 2019, p. 1, first paragraph) for the prevention or reduction of ICI-therapy-induced colitis. Montfort et al. have initiated a phase Ib clinical trial looking at two different ICBs and the TNF inhibitor infliximab or certolizumab. These TNF inhibitors are only being investigated for their safety with ICBs and ability to reduce/eliminate ICB immune-related adverse effects (p. 3, first and second paragraphs). Additionally, there is no written description for an immunotherapy that is not directly a TNFα, TNFR1 or TNFR2 inhibitory antibody or trap (i.e., a Fc fused to the ligand or receptor, e.g., etanercept) and that is a TNF inhibitor that could be used in the claimed method (however, see rejection below relating to lack of support for TNFR1 inhibitors).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. § 112(a), e.g., not for nucleic acids or derivatives thereof, small molecules, cell therapy or immunotherapy that is not an anti-TNFα or anti-TNFR2 antibody or trap. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1-4, 7 and 9-11 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.
The claims are drawn to a method for treating neuroblastoma in and individual by administering one or more tumor necrosis factor (TNF) inhibitors. As recited in claim 3, the TNF inhibitor comprises a TNFα inhibitor, a TNFR1 inhibitor and/or a TNFR2 inhibitor. There are two forms of TNFα, a soluble (sTNFα) which binds TNFR1 and a membrane-bound (mTNFα) form which binds TNFR2 ([0144]). The specification showed that etanercept, a Fc:TNFR2 fusion, bound and neutralized both TNFα forms ([0025]). However, the effects of each form and each receptor is not the same. Both Fig. 4A-B and 14D show results with TNFR knock out (KO) cells, with only TNFR2 KO cells shown to be critical for monocyte activation ([0019] and [0029]). Consistent with this, in Example 13 using monocytes co-cultured with NB cells having each receptor separately knocked out it is stated ([0146]), “These findings demonstrate that NB TNFR2 is crucial for induction of IL-6 production in monocytes, consistent with the observation that mTNFα mediates this induction on the monocytic side.” Although with the same co-culture, treatment with TAPI, a TACE inhibitor that inhibits conversion of mTNFα to sTNFα, increased IκBα expression, representing a decrease in NF-κB signaling ([0147]), though the IκBα expression level was still significantly below that produced by NB cells (Fig. 23C). This latter finding suggest sTNFα is important for NF-κB signaling ([0147]). Example 6 shows monocyte-NB co-culture treated with TAPI still had significant stimulation of IL-6 production, indicating monocyte activation (Fig. 5A-B). The inhibition had no effect on IκBα expression (an inverse measure of NF-κB signaling, a pro-survival signal, in NB cells). In contrast (Ex. 13), a different co-culture experiment with TNFR1 and -2 KO NB cells found only TNFR1 affected NF-κB signaling as measured by IκBα expression (Fig. 14E). It was also found ([0151]) that etanercept applied to monocyte-NB co-culture “effectively disrupts the mTNFα/TNFR2 signaling axis between NB cells and monocytes, preventing NF-κB activation in both cell types. This reduces the production of pro-tumorigenic cytokines by monocytes, ultimately resulting in decreased proliferation of NB cells in vitro.” Because etanercept binds both forms of TNFα (as well as LTα, a.k.a. TNFβ), results from its use cannot distinguish between the role of the different receptors. While etanercept antitumor activity was shown in vivo with a mouse engrafted with CHLA0225-Luc and monocytes embedded in Matrigel (Example 15), this does not distinguish between the effect of the two different receptors. The correlation of high tumor expression of TNFR1 with poor event-free 5-year survival ([00126]) also does not show that inhibition of TNFR1 activity can treat neuroblastoma. These experiments point to a major role of TNFR2 in neuroblastoma and potentially a minor role for TNFR1. This in combination with the requirement of the claims for treatment of neuroblastoma and the specification having shown only “treatment”, i.e., in vivo effects, with etanercept, it does not appear an agent that inhibits only TNFR1 and not TNFR2 meets the written description requirements of 35 USC 112(a). Along the same lines, an inhibitor that inhibits only sTNFα and not mTNFα does not meet the written description requirements. Note that there is also a distinct TNF protein called TNFβ or LTα, which the specification does not mention. There is no written description for wherein the TNF inhibitor of the claimed method is a TNFβ inhibitor.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Therefore, only a direct TNFα or TNFR2 inhibitor (commensurate with the separate rejection above also addressing written description), but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-5, 7 and 9-11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gesundheit et al., J. Clin. Oncol. 25(33): 5321-5124, 2007 (cited in the PTO-892 mailed 7/2/25)
Gesundheit et al. teach treatment of a pediatric patient with neuroblastoma (NB) by oral administration of thalidomide for 6 months, resulting in clinical improvement, including resolution of symptoms (p. 5322, col. 1, and col. 2, lower third). Thalidomide was administered sequentially, i.e., after, with chemotherapeutics and high-dose radiation to treat NB (p. 5322, col. 1).
Claim(s) 1-11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2007049043 A1 (cited in the IDS filed 4/7/25).
WO 2007/049043 teaches in claims 1, 15-17, 8 and 14-17 a composition comprising a TNFα or TNFR2 inhibitor and use thereof for treatment of a tumor which is neuroblastoma. It teaches that NGF (nerve growth factor) induces expression of TNFα (tumor necrosis factor alpha) and that TNFα activates receptor TNFR2, which in some contexts promotes proliferation (p. 4, lines 1-6 and 22-24). Two different neuroblastoma cell lines treated with pro-NGF and anti-TNF signals differentiated (p. 41, lines 1-9). It is shown that NGF induces synthesis of TNFα in neuroblastoma-derived neural cell lines, and it is theorized that this NGF-induced TNFα activates TNFR2, promoting survival and proliferation, including in neuroblastoma cells (e.g., p. 5, lines 20-31). “The anti-proliferative, pro-differentiation effects that we observe upon applying a combination of pro-NGF and anti-TNFα agents to neuroblastoma cells indicate that inhibition of TNFα pathway has the potential to treat cancer and other proliferative disorders of cells,..” (p. 7, lines 1-6) “We propose employing a combination of NGF and an inhibitor of TNFα signalling in new therapeutic strategies for neuroblastoma.” (p. 41, lines 8-9) This approach is important for treating middle- and high-risk neuroblastomas (p. 8, lines 1-3). An anti-TNFR2 antibody and anti-TNFα antibody are disclosed (p. 13, line 26, through p. 14, line 5). Other TNFα inhibitors are listed on p. 16, lines 27-35, including infliximab, etanercept, adalimumab, all proven to be clinically acceptable for treatment of humans, and thalidomide. The inhibitors may be administered intravenously (e.g., p. 22, lines 20-24). Administration may further comprise a pro-NGF agent that is administered simultaneously or sequentially (p. 22, lines 1-6). Neuroblastoma is stated as being most commonly observed in infancy and childhood (p. 1, lines 16-17). The compositions may be used to treat a human (p. 20, lines 4-5).
Note that since neuroblastoma most commonly occurs in children, the human patient may inherently be a pediatric patient.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-5, 7 and 9-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brown 2008 (cited in the IDS filed 9/26/2022), Golliot et al.(Canc. Res., 52(11): 3194-200, 1992), US 20190255050 A1 (Habib, cited in the IDS filed 04/29/2024) in view of Cheung et al.(Nat. Rev. Cancer, 13:397-411, June 2013).
Brown teaches a clinical study treating patients with a variety of advanced cancers by administration of infliximab, a TNFα inhibitor. Both tumor and stromal cells in the tumor microenvironment in a variety of solid and haematological cancers have increased TNFα expression (p. 1340, sentence bridging cols. 1-2). Infliximab inhibits TNFα binding to its receptors and it has been used for treating a number of inflammatory diseases, while reducing cytokine and growth factors involved in tumor growth, invasion and metastasis (p. 1340, col. 2, middle, and p. 1341, first paragraph). Infliximab was administered by intravenous infusion to 41 patients with a variety of advanced cancers, the tumor type of 14 of the patients simply listed as “all other tumours” (Table 1, and p. 1341, col. 1, “dosing and administration”). Seven patients showed stable disease after treatment and no plasma TNFα, in contrast to 17/34 patients who had detectable plasma TNFα and progressed during therapy (p. 1342, col. 1, third paragraph, and p. 1344, col. 1, first paragraph). It is also reported that TNFα inhibitor etanercept treatment resulted in stable disease or partial response in patients with haematological, breast or ovarian cancer (p. 134 5, col. 1, third paragraph). Brown et al. does not teach treatment of neuroblastoma or treatment with another therapy.
Golliot et al. teaches that in two neuroblastoma cell lines TNF application caused proliferation; however, a TNF-blocking antibody blocked survival of the cells. An antibody to TNFR1 or TNFR2 (types A and B receptors) did not or only partially blocked NB growth, but both together blocked over 85% of growth (p. 3199, col. 1, third full paragraph, and Fig. 4). Administration of TNF antagonists for NB is suggested (p. 3199, col. 2, fourth paragraph).
Habib teaches in paragraphs [78]-[80] and Fig. 24, addition of thalidomide, a TNF inhibitor, to erlotinib, an EGFR inhibitor, treatment led to greater tumor volume inhibition than erlotinib alone in a lung tumor xenograft mouse model. Treatment of neuroblastoma with this method is suggested ([0080]).
Cheung et al. teach neuroblastoma is a childhood cancer (p. 397, col. 1, first sentence). Anti-GD2 antibodies have been used for treatment of neuroblastoma, leading to complete remission, and has become the standard of care (p. 404, col. 2, third paragraph).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention to have treated a human child suffering from neuroblastoma and a TNF inhibitor such as infliximab or other TNF-blocking antibody because Brown et al. taught the effectiveness of infliximab in treating a variety of cancers. Further Golliot et al. taught in vitro that TNF-blocking antibodies blocked NB cell survival, consistent with the blocking of NB growth for neuroblastoma cells treated with antibodies binding and blocking TNFR1 and TNFR2 activity. Consistent with the antitumor activity of a TNF inhibitor, Habib taught that in vivo TNF inhibitor thalidomide resulted in greater decrease in tumor volume when used with EGFR inhibitor erlotinib than when treatment was only with erlotinib. Further, Habib suggests treatment of neuroblastoma with erlotinib and thalidomide. The combined teachings of the prior art provide a reasonable expectation of successful treatment of neuroblastoma with a TNF inhibitor and optionally with another therapeutic agent concurrently or sequentially, such as with an anti-GD2 antibody, which Cheung et al. taught is the current standard of care for neuroblastoma.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
US Patent 9,642,819 treated human neuroblastoma cells with a 5-HTA agonist and showed a decrease in a proinflammatory marker, inhibited TNFα-induced inflammation in multiple cell types including human neuroblastoma cells, and inhibited TNF-induced IL-6 expression in rat primary aortic endothelial cells (col. 4, lines 1-8, and Example 9).
ClinicalTrials.gov ID NCT03294954 describes a study for treating of pediatric neuroblastoma with GD2-specific chimeric antigen receptor- and IL-15-expressing autologous NKT cells. However, it is not until 2023 that mention of treatment with etanercept also occurs (v9 vs. v18).
Balza et al. (Int. J. Cancer, 127(1):101–110, 2010, p.101, col. 2, middle of first paragraph) teaches away from the instant invention by noting that TNFα has an antitumor effect through preferential toxicity for endothelial cells of tumor vasculature, “resulting in extensive tumor necrosis, and through an increase of the antitumor immune response.13-16” Using a neuroblastoma mouse model, Balza et al. states:
We generated the fusion proteins L19-IL223 and L19mTNFa, 24 conjugating L19(scFv) with human IL-2 and mouse TNFα (m TNFα), respectively. When injected intravenously (i.v.) into tumor-bearing mice these fusion proteins selectively accumulate around the tumor vasculature23,24 where they can exert their anticancer activities. For the tumor-targeting and preclinical therapeutic performances,22–24 these fusion proteins are presently undergoing testing in phase I/II clinical trials.26,27
Both fusion proteins showed anticancer therapeutic effects that are synergistically, enhanced by combined treatment in preclinical studies.24
The L19 antibody fragment portion of the fusion was used for NB targeting (p. 106, col. 2, third paragraph). It was also shown that a protective antitumor immune response was long-lasting and “could be transferred to naïve recipients by adoptive cell transfer of immune T cells.” (p. 107, col. 1, second paragraph)
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
January 16, 2025