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 .
Claim Status
Claims 1, 57, 59, and 63-64 are currently pending in this application.
Election/Restrictions
The election of Group I, claims 1-16, 57, 59, and 63-64, in the reply filed on Aug. 8, 2025 is acknowledged. Acknowledgement is made of applicant’s election of the species of antibody light chain constant domain that has the CK (κ or kappa) sequence consisting of instant SEQ ID NO: 1 and the oncological disease bladder cancer. Claims 1, 57, 59, and 63-64 have been considered on the merits and all arguments were fully considered.
Previous Rejections
Status of the rejections: the previous rejections pursuant to sections 102 and 103 are withdrawn in view of the claim amendments.
Claim Interpretation
In claim 1, the phrase “based on IL-15/IL-15Rα” is interpreted as non-limiting as the definite structural limitations recited in the claim limits the immunocytokine protein complex to comprising at least two different polypeptides, one comprising IL-15Rα and the other comprising IL-15. Thus, the presence of both IL-15 and IL-15Rα components in the complex fully satisfies all that is implied by “based on IL-15/IL-15Rα.”
In claim 1, the term “linked” is interpreted as meaning as a fusion polypeptide, either directly or indirectly, such as via a linker or hinge as in dependent claim 10, and to accommodate the claim 1 phrases “linked to” “antibody heavy chain constant domains.” Note this interpretation excludes a covalent S-S bridge as satisfying the meaning of “linked.” Note, claim 1 does not expressly preclude wherein the IL-15Rα and IL-15 components of the immunocytokine are linked, i.e., as a fusion protein; however the term “heterodimeric protein complex” in view of the instant specification is interpreted as excluding any such fusion protein.
In claim 1, the phrase “has the amino acid sequence represented by” is interpreted to mean “consists of.”
In claim 1, the term “natural S-S bridge” with regard to a covalent association between antibody chains is interpreted to mean any inter-chain disulfide bond between paired cysteine R-groups regardless of position as the claimed protein complex is not natural and its components are neither natural nor complex by any “natural” bridge.
Claim Rejections - 35 USC § 112(a), Written Description (modified)
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, 57, 59, and 63-64 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
When the claims are analyzed in light of the specification, the instant invention is directed to an immunocytokine (IL-15/IL-15Rα protein or heterocomplex) capable of stimulating the activation and/or proliferation of IL-15R+ (“IL-15Rbeta/gamma” (β/γc) - positive) cells. Further, the invention of claim 64 is broadly directed to a pharmaceutical composition comprising said immunocytokine capable of use in treating an oncological disease selected from specifically recited ones.
Claim 1 is broad in that although the heterodimeric protein complex comprises a covalent association via a disulfide bridge, the complex is unlimited as to whether it comprises any other associations, e.g., IL-15 with IL-15Rα. It must also be emphasized that the scope of the invention of claims 64 encompasses all the specifically recited diseases; however, there is insufficient written description in the specification to reasonably convey to one skilled in the relevant art at the time the application was filed that the inventors had possession of the entire scope of immunocytokine heterodimeric protein complexes capable of stimulating the activation or proliferation of IL-15R+ cells encompassed by claim 1, such as any immunocytokine species thereof for use in treating all the recited diseases of claim 64.
Claim 64 is broad in that it encompasses diverse oncological diseases, e.g., afflicting diverse organs as the brain, cervix, colon, liver, lung, ovary, pancreas and prostate, and/or with unknown primary origins.
Firstly, the prior art is silent as to any IL-15R+ cell stimulating protein complex comprising SEQ ID NO: 1 and 2 covalently connected by a disulfide bond. Secondly as explained below, there is a lack of evidence applicant had possession of an immunocytokine heterodimeric protein complex comprising both SEQ ID NO: 1 and 2 that stimulates activation and proliferation of any IL-15R+ cell in the absence of IL-15 binding to IL-15Rα, either in cis or trans. Rather, the instant specification notes that IL-15 binding to IL-15Rα via its Sushi domain is essential for its biological activity ([0006]).
Third, the prior art is silent as to any treatment-effective complex comprising IL-15Rα linked to an antibody light chain constant domain and IL-15 linked to an antibody heavy chain wherein the IL-15Rα and IL-15 are covalently connected by a disulfide bond. Fourth, there is a lack of evidence in the instant specification as filed that the inventors were in possession of an immunocytokine complex in a pharmaceutical composition for the treatment of any oncological disease beyond treating a melanoma tumor/cancer (B16F10) comprising no actually described excipient(s) (instant Examples 11-12; FIG. 23-25).
The written description requirement may be satisfied through actual reduction to practice or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of such a broad genus. For example, whether empirical data shown in the instant application wherein IL-15 partners with IL-15R to stimulate activation and proliferation of IL-15R+ cells can be extrapolated to other heterodimeric protein complexes where they cannot associate with each other instead of as in the prior art relying on the self-assembling non-covalent attachment of IL-15 and IL-15Rα-sushi domain. Similarly, whether the results shown in instant Examples 11-12 (FIG. 23-25) can be extrapolated to other diseases due to a nexus between the effective amount of the immunocytokine structure used and the treatment of such oncological diseases and further as to the choice of excipient(s).
In the instant case, the specification fails to provide sufficient descriptive information. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed to possess such diversity in immunocytokine structure regarding IL-15Rα/IL-15 association and all the treatments for such diverse oncological conditions. Instead, the instant specification merely describes generic and prophetic methods of treating various cancers comprising administering “an effective amount” of the claimed immunocytokine complex without description of the treatments themselves (e.g., if another active agent is present beyond the complex) or as to how stimulating activation or proliferation of IL-15R+ cells contributes to such diverse treatments to determine any treatment use.
Dependent claims 57, 59 and 63 are deficient for the same reasons as claim 1. Further regarding claim 57, as the immunocytokine is required to comprise a covalent association through a natural S-S bridge but this structure is not encodable by a nucleic acid, the specification fails to provide sufficient descriptive information of possession of any such isolated nucleic acid.
Of the diseases recited in claim 64, the leukemic subtypes are particularly different from melanoma, both in being cancers of immune cells (some of which express IL-15R and IL-15) and in not forming solid tumors as do all the other recited species. The instant descriptions provides no guidance to translating or adapting the described melanoma treatment across the scope of all recited diseases, e.g., any leukemia.
The instant specification merely describes generic and prophetic treatments of various cancers comprising administering “an effective amount” of the claimed immunocytokine complex without description of the treatments themselves (e.g., if another active agent is present beyond the complex) or as to how stimulating activation or proliferation of IL-15R+ cells contributes to such diverse treatments to determine any treatment use.
While the prior art teaches using IL-15 agonist immunocytokine complexes in treatment methods wherein there is either intra-antibody chain covalent disulfide bonds but no covalent linkage between the IL-15 and IL-15Ra components (“IL-15:sIL-15Rα/Sushi-Fab/Fc” as in ALT-803, RLI, 2B8T2M, or KENP024116) or the components are covalent linked together as a single fusion protein without any antibody components (IL-15:sIL-15Rα heterodimer) (Zhao et al., Biomed Pharmcother 112: 108677 (2019) at Fig. 1, pg. 5, right col., to pg. 6; Fig. 5-6; Liu et al., J Biol Chem 291: 23869-81 (2016) at Fig. 1, 7-9; Bernett (WO2019006472A1) at [00549]; FIG. 76-78, [00109]-[00111]), the prior art does not guide as to in vivo predictability for the presently claimed structure and any oncological disease. The treatment evidence in the prior art (e.g., regarding colon cancer or lymphoma xenografts) is not for any complex comprising both a IL-15 antibody fusion and a “natural S-S bridge” covalently attaching an antibody heavy chain constant domain and a light chain constant domain but rather specific to the structures known in the art, which differ significantly from the presently claimed structures.
Therefore, the skilled artisan cannot envision from the written description a functional immunocytokine complex wherein the IL-15Rα and IL-15 components are SEQ ID NO: 1 and 2 but not bound with each other, or any pharmaceutical composition thereof, having a use for stimulating the activation and/or proliferation of an IL-15R+ cell. Further, the skilled artisan cannot envision from the written description any composition having a use for the treatment of an oncological disease beyond melanoma. For example, the specification does not provide any disclosure as to how to translate the possessed melanoma treatment with reasonable predictability to all other oncological treatments recited in claim 64, e.g., a leukemia. Instead, the claims encompass diverse cancers without evidence or even description of a speculative nexus across treatments and diseases. Thus, for many of the diseases encompassed by this claim, a treatment-effective version of the claimed pharmaceutical composition is not reasonably predicted to exist without further evidence.
35 USC § 112(a), Scope of Enablement (modified)
Claim 64 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while the claims are enabled for an therapeutically effective amount of immunocytokine which stimulates the activation or proliferation of IL-15 receptor positive cells for the treatment of melanoma, the specification does not enable any person skilled in the art to which it pertains or with which it is most nearly connected to us the claimed immunocytokine complex to treat all the other oncological diseases recited.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue or unreasonable experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The 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 required is “undue” or unreasonable 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.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature and Breadth of the invention:
The claim is directed to pharmaceutical compositions comprising an excipient(s) and a specifically recited immunocytokine heteroprotein complex for the treatment of a list of specifically recited oncological diseases.
The state of the art:
The prior art teaches using IL-15 immunocytokine complexes ("scIL-15/Rα(sushi) Ig Fc fusion complexes) comprising IL-15Rα and IL-15 linked to antibody chain constant domains and having antibody chain disulfide bridge covalent bonds for treating a variety of cancers and tumors (Bernett at FIG. 30, 16, 57, and 80; [0006], [0015], [00186], [00252], [0011], [00479]-[00480]; [00433]). However the prior art is silent to wherein the complex specifically comprises SEQ ID NOs: 1 and 2.
The prior art also teaches oncological treatments comprising administering IL-15/IL-15Rα superagonist complexes (ALT-803 and variants thereof (2B8T2M)) related to the presently claimed structure but engineered for enhanced IL-15 receptor activation with increased affinity and stability/half-life and/or mimicking transpresentation in vivo at doses of at least 0.3-50 µg/kg of recipient or 10, 30 or 100 µg total in xenograft tumor models or patients (Rhode et al., Cancer Immunol Res 4: 49-60 (2016) at Fig. 1, pg. 59, left col. para. 2-3, abstract (recommending repeated IV administrations at 1-10 µg/kg for patients); Rosario et al., Clin Cancer Res 22: 596-608 (2016) at Fig. 4-5 (mouse xenograft models of lymphoma receiving repeated administrations at 0.05-0.2 mg/kg via IV along with rituximab); Liu et al., J Biol Chem 291: 23869-81 (2016) at Fig. 7B,E, Fig. 8 (mice receiving repeated IV administrations); Felices et al., Gynecol Oncol 145: 453-61 (2017) at pg. 454, right col., last para., to pg. 455 left col., 1st para., Fig. 6D-G (mouse xenograft model of ovarian cancer receiving repeated administrations at 50 µg/kg subcutaneously or intraperitoneally); Wrangle et al., Lancet Oncol 19: 694-704 (2018), IDS ref., at pg. 696, right col., para. 2-4, pg. 699, left col., para. 2-4, Table 3, Fig. 2 (NSCLC lung cancer patients coadministered nivolumab receiving repeated IV administrations of 6-20 µg/kg subject); Zhao et al., Biomed Pharmcother 112: 108677 (2019) at pg. 5, right col., to pg. 6; Fig. 5-6 (mouse colon cancer xenograft); Pinette et al., Cancer Immunol Immunother 68: 1379-89 (2019) at pg. 1381 right col., para. 4, pg. 1385, right col., last para., Fig. 7 (mouse xenograft cancer model receiving repeated administrations with or without cetuximab). The prior art teaches that large amounts of IL-15 superagonist can cause various toxicities, including the potential for inducing life-threatening cytokine storms (id.).
However the prior art is silent as to any oncological treatment (e.g., administering a treatment effective amount for any oncological condition) comprising a disulfide bridge based complex comprising IL-15Rα linked to an antibody light chain constant domain and IL-15 covalently linked to an antibody heavy chain wherein the complex comprises instant SEQ ID NOs: 1 and 2. Thus, the prior art is silent as to any analysis of dosage limiting toxicities in such an oncological treatment required to determine such a treatment. The prior art is also silent as to wherein the IL-15 and IL-15Rα components do not either self-assemble via a non-covalent attachment of the IL-15 and a sushi domain of the IL-15Rα component or further enhanced by covalently binding the IL-15 directly to the IL-15Rα component.
As the prior art does not teach treatments for any oncological disease with an effective amount of the recited immunocytokine structure, these aspects must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention of claim 64 without any undue burden being on such an artisan.
The amount of direction and guidance and working examples provided by Applicant:
The instant application provides generic guidance by describing methods of making pharmaceutical compositions for stimulating activation and proliferation of IL-15R-positive cells during the treatment of an oncological disease (instant pg. 17-19 and 76-87). A single generic working example is provided at instant Examples 11-12 using intraperitoneal injection of a single embodiment comprising an unnamed excipient(s) (e.g., perhaps PBS) in the treatment of mice inoculated with a B16F10 melanoma tumor line in a mouse xenograft model of cancer.
Thus, there is no evidence provided in the application that the claimed composition could be predictable used in a treatment of any other oncological disease. Of the diseases recited in claim 64, the leukemic subtypes are particularly different from melanoma, both in being cancers of immune cells (some of which express IL-15R and IL-15) and in not forming solid tumors. The instant descriptions provides no guidance to translating or adapting the described melanoma treatment across the scope of any leukemia. Instead, the instant specification merely describes prophetic methods of treating any cancer with any pharmaceutical composition comprising the claimed immunocytokine and any excipient, and which may comprise administering by any route despite the diversity of cancer sites: brain (glioblastoma), cervix, colon, liver, lung, ovary, pancreas and prostate, and/or cancers of unknown primary origins which are presumably in any location.
The quantity of experimentation needed to make and/or use the invention:
Extensive experimentation would be required to determine how to make and use a pharmaceutical composition comprising any excipient and for any route of administration when treating each of the oncological diseases recited. The science of medicine has not evolved such that, without guidance or working examples in the specification regarding a nexus between formulating and administering the immunocytokine and treating any such oncological disease (e.g., a leukemic disease), one can perform the full scope of the claimed method without undue and unreasonable experimentation, which may never be achieved across the entire scope of claim 64. In particular, extensive experimentation would be required to determine how to create treatments for each oncological disease recited based merely on melanoma, e.g., in as melanoma-diverse organs as the brain, cervix, liver, lung, ovary, and prostate. A therapeutic nexus was demonstrated using a immunocytokine as claimed only for mouse melanoma using a single route of administration and without a description of the excipient(s) present; however applicant is invited to furnish evidence to the contrary.
Response to Arguments
Applicants remarks filed Feb. 28, 2026 contained no substantive argument as to why the previous section 112(a) rejections were overcome.
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.
Claims 1, 57, 59, and 63-64 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 pre-AIA the applicant regards as the invention.
Claim 1 and 63 each recites the term “IL-15Rbeta/gamma-positive cells”, which is ambiguous and unclear as to the purpose of the slash and the items before and after it. Are the cells limited to being either IL-15Rbeta positive or IL-15Rgamma positive, or alternatively, must the cells be positive for both IL-15Rbeta and IL-15Rgamma? Claims 57, 59, and 64 are included in this rejection for depending from indefinite claim 1 and/or 63.
Response to Arguments
Applicants remarks filed Feb. 28, 2026 were not found persuasive. Nowhere does Stonier et al. (2010) use the term “IL-15Rbeta/gamma-positive” to describe a cell type. Instead, Stonier uses the term IL-15Rα+ cell (e.g., DCs). Thus, the evidence in the record lacks any indication a person of ordinary skill in the art understands the term “IL-15Rbeta/gamma-positive” and its metes and bonds, including at least the meaning of the slash symbol. For example, must the cells be IL-15Rα+ (i.e., CD215 complexed with IL-15R beta and gamma)? It would be remedial to amend the term to “IL-15R β/γc positive cells” or “IL-15R β/γc-positive cells” or “CD122/CD123 positive” cells or “CD122+/CD123+” cells, or simply “CD15 receptor”-positive cells.
Conclusion
No claim is allowed.
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 ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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