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
Acknowledgement is hereby made of receipt and entry of the communication filed on Nov. 20, 2023.
Claims 3-8 are amended.
Claims 9-19 are new.
Claims 1-19 are pending and currently examined.
Detailed Action
Information Disclosure Statement
The information disclosure statement (IDS) filed on 02/05/2024 and 09/25/2025 are considered, initialed and are attached hereto.
Priority
Applicant’s claim for the benefit of priority to U.S. Provisional Patent Application No. 63/115,393, filed on November 18, 2020, is acknowledged.
Objection to the Drawings
The drawings are objected to because : a). Fig. 1B shows tumor volume rather than mouse survival analysis as stated in brief description of drawings (para. 6); b) data in Fig. 1B show IFNAR1 mAb (monoclonal antibody) blocked the effect of PD-1 mAb, but the specification states blockage of IFNAR1 signaling had no effect (para. 45); c) the treatment condition PD-1 mAb have inconsistent labeling of PD-1 mAb or PD-1 in different figures; d) brief description states there are two graphs (left and right) in Fig. 2C (para. 7) but only one graph is included in the drawings; e) specification explain Fig. 3B shows PD-1mAb inhibited the growth of the ICI-resistant tumor, but since this is a tumor model with both ICI-sensitive and ICI-insensitive cancer cells, the conclusion cannot be made; f) there is no CD3+ (without early IFNAR1 mAb) only control group, the effect of tumor inhibition is hard to interpret for the treatment group "PD-1 mAb+ CD3" because the effect could be due to CD3+ cells alone or synergic effect of PD-1 mAb and CD3+ cells; g) two different Fig. 4B are described in the specification (para. 48) but only one Fig. 4B is included in the drawings.
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.
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.
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.
Claim 1-19 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or 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 the Applicant was in possession of the claimed genus.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicant are claiming and what Applicant have possession of.
The claims are drawn to a method of administering a Type I interferon (IFN) and an immune checkpoint inhibitor (ICI) to a subject to increase sensitivity of the tumor to a host immune response. In claim 2, the ICI is a PD-1 inhibitor. In claims 3-19, the ICI is an anti-PD-1 antibody. In claims 6, 10-15 and 18-19, the type I IFN is IFN-α. In claims 5 and 16-19, the tumor is a glioma.
The specification explains sensitivity refers to the way a tumor reacts to a therapeutic (such as ICI inhibitor) or a host immune response (inst. specs. para. 21). A tumor that is sensitive to host immune response means the tumor is recognized by the host immune system and subject to attack by immune effector cells (para. 21). Improving or increasing sensitivity of a tumor means the tumor become responsive to a treatment or host immune response from the state of resistant (non-responsive, or refractory), have improved response compared with other or previous treatment, become responsive to the treatment at a lower dose, or achieving better therapeutic effect at the same dose (para. 21). The sensitivity can be measured by increases in the number of immune effector T cells, the killing of cancer cells, and/or enhanced T cell survival, secretion, activity and longevity (para. 22).
The specification states that an ICI can be a small molecule, an inhibitory nucleic acid, an inhibitory polypeptide, or an antibody or antigen-binding domain, that decreases, blocks, inhibits, abrogates or interferes with the function of any protein of an immune checkpoint pathway, such as PD-1, CLTA-4, CD28, ICOS (inducible T-cell co-stimulator, aka CD278), B7-1 (aka CD80) and B7-2 (aka CD86) (para. 13-20).
The specification lists some examples of PD-1 inhibitor, including antibodies that bind with PD-1, a small peptide AUNP-12 (NP-12) and a fusion protein AMP-224 (inst. specs. para. 19). AUNP-12 is derived from PD-1 and binds to PD-L1/L2 (Sasikumar et al Mol Cancer Ther (2019) 18 (6): 1081-1091). AMP-224 only binds to T cells expressing high levels of PD-1 but not T cells expressing low levels of PD-1, which leads to clearance of these T cells (Smothers et al, Annals of Oncology 24 (supplement 1): i7-i17 2013). Therefore, the scope of PD-1 inhibitor is interpreted as any molecules that inhibit PD-1, PD-L1, PD-L2, or a combination of. The molecule could be a small molecule, a nucleic acid, a peptide, a fusion protein, or an antibody.
The subject is a mammal, including but not limited to rodents, bovines, swine, horses, primate and human.
Therefore, the claims recite using any type I IFNs and any inhibitors against any proteins in the immune checkpoint pathway (or any inhibitors against PD-1/PD-L1/PD-L2, or any anti-PD-1 antibodies), to increase the sensitivity of any types of tumors (or glioma) in any mammals.
The specification has written description for following example: administering IFN-α and antibodies inhibiting PD-1 pathway (PD-1 blockade) to a B16F0 melanoma mouse model in vivo, increases the survival of the mice and reduces the tumor size, compared with mice that are untreated or only receiving PD-1 blockade (Fig. 4 A-B). Since this tumor does not respond or respond poorly to PD-1 blockage alone, the example shows the method improves sensitivity of the B16F0 melanoma in mouse in vivo (Fig. 4 A-B). The specification fails to disclose the specific antibody, whether anti-PD-1 (RMP1-14), anti-PD-L1 (10F.9G2), or both, is used in the example. Therefore, it is unclear which antibody achieved this effect in Fig 4 and the results are interpreted as achieved by blocking the PD-1/PD-L1/L2 pathway (PD-1 blockade), which could be achieved by either the anti-PD-1 antibody, the anti-PD-L1 antibody, or combing both. If only anti-PD-L1 (10F.9G2) is used, the speciation provides one example of the ICI (anti-PD-L1 antibody) and a PD-1 inhibitor (anti-PD-L1 antibody), but not an example of anti-PD-1 antibody. If only anti-PD-1 (RMP1-14) or a combination of both antibodies is used, the specification provides one example of the ICI (anti-PD-1 RMP1-14 antibody, or both anti-PD-1 RMP1-14 and anti-PD-L1 10F.9G2 antibody), PD-1 inhibitor (anti-PD-1 RMP1-14 antibody, or both anti-PD-1 RMP1-14 and anti-PD-L1 10F.9G2 antibody), and an anti-PD-1 antibody (anti-PD-1 RMP1-14 antibody). However, the specification does not have written description for using all types of type I IFNs and all types of inhibitors against any proteins in the immune checkpoint pathway (or all inhibitors against PD-1/PD-L1/PD-L2, or all anti-PD-1 antibodies) to increase sensitivity of all types of tumors.
The claimed invention encompasses the use of any type I IFN and any inhibitors against any proteins in the immune checkpoint pathway (or any inhibitors against PD-1/PD-L1/PD-L2, or any anti-PD-1 antibodies) to increase the sensitivity of any tumor. A brief assessment of the state the art regarding Applicant’s is made herein.
The function of inhibitor against the protein in the immune checkpoint pathway, PD-1/PD-L1/PD-L2 inhibitors, or PD-1 antibodies, in cancer treatment, is dependent on the reagent and the type of tumor. Inhibition of the co-inhibitory protein in the immune checkpoint pathway (such as PD-1 and CTLA4) is the target of cancer immune therapy, inhibition of co-stimulatory protein of immune checkpoint pathway, such as CD28 and ICOS (inducible T-cell co-stimulator, aka CD278), is often associated with reduced immune response because T cells require co-stimulatory signals for optimal proliferation, differentiation and survival (O’Neill and Cao, Adv Cancer Res. 2019 Apr 17; 143:145-194). For instance, Amatore et al (Expert Opin. Ther. Targets 22:4, 343-351) teaches that ICOS have both pro-tumoral and anti-tumoral role, and the choice of specific therapy would be based on immunological criteria such as whether ICOS is expressed mainly by tumor cells or by cytotoxic T cells (p.348, section 6 conclusion). If ICOS is mostly expressed in the T cells in a specific tumor type, an inhibitor is likely to promote the tumor growth (p.348, section 6 conclusion).
Despite PD-1 and PD-L1 inhibitors share the same function of blocking the PD-1/PD-L1 pathway, there is difference in the structure and clinical outcome (Chen et al, Front. Immunol, 11:1088). For instance, while both pembrolizumab and nivolumab have shown survival benefits in patients as monotherapy, pembrolizumab showed survival benefits for non-small cell lung cancer but nivolumab did not (Chen et al, p.6 right column last para.). Similarly, when administrating IFN-α and PD-1 antibody to patients, one trial shows the method is safe and effective in PD-1 naïve melanoma patient (Davar et al, J Clin Oncol. 2018 Oct 25; 36(35):3450-3458), but another trial shows limited antitumor activity at the maximum tolerated dose in patients with advance melanoma or renal cell carcinoma (Atkins et al, Clin Cancer Res (2018) 24 (8):1805-1815). Many small molecule inhibitors against PD-1/PD-L1 are being developed and tested, but the first oral PD-L1 inhibitor to enter clinical testing has been discontinued for toxicity reasons (News in Brief, “Oral PD-L1 inhibitors crowd into the clinic, Cancer Discov (2023) 13(1): OF2).
In addition to the unpredictability with immune checkpoint therapy treating different types of cancer, Sharma et al (Cell, 186 (8), 1652-1669) teaches there are other challenges that remained to be addressed, such as resistance to the therapy (p.1657-1659), and development of severe or even fatal immune-related adverse events (irAEs)(p. 1659-1660). In addition, there are significant variability in the effective of the therapy between patients, that could be correlated with high tumor mutational burden or PD-L1 expression (Cristescu et al, JITC, 2022:10:e003091 and Zhao et al, Ther Adv Med Oncol, 2020, 12:1-22).
Taken together, the state-of-the-art support the position that not all types of inhibitors against the protein in the immune checkpoint pathway, PD-1/PD-L1/PD-L2 inhibitors, or PD-1 antibodies would have the same function in all types of tumors. It would not have been apparent to one skilled in the art that administering any type I IFNs and any type of inhibitors against the protein in the immune checkpoint pathway (or any inhibitors against PD-1/PD-L1/PD-L2, or any PD-1 antibodies) may result in an increase in the sensitivity of any type of tumors in any mammals.
Claims 5 and 16-19 recite administering any type I IFNs (or IFN-α) and any inhibitors against any proteins in the immune checkpoint pathway (or anti-PD-1 antibodies), to increase the sensitivity of gliomas in any mammals.
The specification teaches that IFN-α signaling is important for the sensitivity to PD-1 blockade in mouse GL261 glioma model (para. 45), but it fails to show if and how administering both type I IFN (or IFN-α) and an inhibitor against the immune checkpoint inhibitor (or an anti-PD-1 antibody) increases the sensitivity of a glioma. Therefore, the specification does not have written description for using all types of type I IFNs (or IFN-α) and all types of inhibitors against any proteins in the immune checkpoint pathway (or all types of anti-PD-1 antibodies) to increase the sensitivity of glioma.
Claims 5 and 16-19 encompass administering any type I IFNs (or IFN-α) and any inhibitors against any proteins in the immune checkpoint pathway (or anti-PD-1 antibodies), to increase the sensitivity of gliomas in any mammals. A brief assessment of the state the art regarding Applicant’s is made herein.
Letchuman et al (Neurosurg Focus. 2022. 52(2): E5) teaches the effect of PD-1/PD-L1 inhibitors varies in different glioma mouse models. For instance, anti-PD-1 antibodies are effective in improving mouse survival in vivo using GL261 glioma models, which have high immunogenicity and high mutational load (Tab 1&2). In CT-2A glioma model, which has low immunogenicity and moderate mutational load, anti-PD-L1 antibodies only modestly improve survival (+4.5 days), compared with 50% long-term survival in GL261 (Tab. 1&2). In another glioma model (SB28), anti-PD-1 does have not curative or survival benefit (tab. 2).
Reardon et al (Cancer Immunol Res; 4(2) February 2016, refer to as Reardon 2016 thereafter) teaches different PD-1 inhibitors have different outcome in improving mouse survival using a GL261-luc2 mouse model. Compared with anti-PD-1 antibody monotherapy, anti-PD-L1 antibody monotherapy is less effective and anti-PD-L2 antibody monotherapy has no effect (p. 126 section Eradicating established glioblastoma tumors and generating long-term survival). Similarly, administering both PD-1 blockade and anti-CTLA-1 antibody have better survival rate compared with PD-1 blockade monotherapy and anti-CTLA-4 monotherapy, but administering both PD-L1 blockade and anti-CTLA-1 antibody has negligible effect compared with the monotherapies (p. 126 section Eradicating established glioblastoma tumors and generating long-term survival).
Despite the effect in some preclinical studies, the clinical trials testing PD-1 antibody monotherapy or in combination with other therapies in treatment of glioma have not shown success (Wang et al, Heliyou 10 (2024) e24729, section 1.10).
This could be due to the fact that similar to other types of cancers, gliomas are heterogeneous at both the molecular and clinical level, and often requires different management and treatment strategies (Nabors et al, NCCN, Central Nervous system cancers, version 3. 2020). For instance, while nivolumab (PD-1 antibody) achieved durable responses in two siblings with bMMRD (biallelic mismatch repair deficiency) recurrent multifocal glioblastoma that had high tumor burden in a Phase 3 clinical trial (Bouffet et al, J Clin Oncol. 2016. 34, 2206-2211) , it only achieved the objective response rate of around 8% (7.8%; 95% CI, 4.1%-13.3%) in recurrent glioblastoma (Reardon et al, JAMA Oncology, 2020. 6(7): 1003-1010, refer to as Reardon 2020 thereafter).
Taken together, the state-of-the-art support the position that not all types of inhibitors against the protein in the immune checkpoint pathway or PD-1 antibodies would have the same function in all types of gliomas that have different molecular profiles. It would not have been apparent to one skilled in the art that administering any type I IFNs and any type of inhibitors against the protein in the immune checkpoint pathway (or any PD-1 antibodies) may result in an increase in the sensitivity of any type of glioma in any mammals.
Therefore, neither the art nor the specification provides a sufficient representative number of species to meet the written description requirement.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed molecules in ICIs, PD-1 inhibitors, or anti-PD-1 antibodies. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the agent per se and thereby the instant application does not provide adequate written description support for which structural features of the molecules would predictably retain their function activities.
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
In Abbvie v. Centocor (Fed. Cir. 2014), the Court noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to Abbvie above. First, the claims clearly attempt to define the genus of ICIs (or PD-1 inhibitors or anti-PD-1 antibodies) by the functions. As noted by Abbvie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed single example would be representative of the entire genus. The specification discloses no structure to correlate with the function.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171). Because the specification does not describe the structures for potentially numerous different ICIs, PD-1 inhibitors or anti-PD-1 antibodies, which would have the recited functions, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all types I IFNs to work with all types of ICI, or all types of PD-1 inhibitors or all types of anti-PD-1 antibodies, to increase sensitivity of all types of tumor (or all types of glioma) to a host immune response.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, there is not identification of any particular portion of the structure that must be conserved or present. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
Claims 1-19 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 improving the sensitivity of melanoma with IFN-α and PD-1 blockade (unclear it is performed by using anti-PD-1 antibody, anti-PD-L1 antibody, or combination of both) in mouse in vivo, does not reasonably provide enablement for increasing the sensitivity of any type of tumor (or glioma) with any type of type I IFN and any type of ICI (or PD-1 inhibitor or PD-1 antibody). 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.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (2) The breadth of the claims:
The claims are drawn to a method of improving sensitivity of a tumor comprising administering a type I IFN (such as IFN-α) and an ICI (or a PD-1 inhibitor or an anti-PD-1 antibody) to a subject.
The specifications teaches that the sensitivity refers to the way a tumor reacts to a therapeutic (such as ICI inhibitor) or a host immune response (inst. specs. para. 21). Improving or increasing sensitivity of a tumor means the tumor become responsive to a treatment or host immune response from the state of resistant (non-responsive, or refractory), have improved response compared with other or previous treatment, become responsive to the treatment at a lower dose, or achieving better therapeutic effect at the same dose (para. 21). The sensitivity can be measured by increases in the number of immune effector T cells, the killing of cancer cells, and/or enhanced T cell survival, secretion, activity and longevity (para. 22).
There are unlimited types of ICIs, PD-1 inhibitors and PD-1 antibodies. There are hundreds of benign tumors and hundreds of malignant tumors (cancers), which have in common only some loss of controlled cell growth. Gliomas are not just one specific type of tumor, but instead heterogeneous at both the molecular and clinical level as well (Nabors et al, NCCN, Central Nervous system cancers, version 3. 2020).
The specification is enabling for the following example: administering IFN-α and antibodies inhibiting PD-1 pathway (PD-1 blockade) to a B16F0 melanoma mouse model in vivo, increases the survival of the mice and reduces the tumor size, compared with mice that are untreated or only receiving PD-1 blockade (Para. 48, Fig. 4 A-B). Since this tumor does not respond or respond poorly to PD-1 blockage alone, the example shows the method improves sensitivity of the B16F0 melanoma in mouse in vivo (Fig. 4 A-B). The specification fails to disclose the specific antibody, whether anti-PD-1 (RMP1-14), anti-PD-L1 (10F.9G2), or both, is used in the example. Therefore, it is unclear which antibody achieved this effect in Fig 4 and the results are interpreted as achieved by blocking the PD-1/PD-L1/L2 pathway (PD-1 blockade), which could be achieved by either the anti-PD-1 antibody, the anti-PD-L1 antibody, or combing both. If only anti-PD-L1 (10F.9G2) is used, the speciation is enabling for one specific ICI (anti-PD-L1 10F.9G2 antibody), and a specific PD-1 inhibitor (anti-PD-L1 10F.9G2 antibody), but not enabling for any anti-PD-1 antibody. If only anti-PD-1 (RMP1-14) or a combination of both antibodies is used, the specification is enabling for one example of the ICI (anti-PD-1 RMP1-14 antibody), one example of PD-1 inhibitor (anti-PD-1 RMP1-14 antibody), and one example of anti-PD-1 antibody (RMP1-14).
The specification does not have enablement for using all types of type I IFNs, all types of ICIs (or PD-1 inhibitors, or PD-1 antibodies), to improve sensitivity of all types of tumors or gliomas in any mammals.
(3) The state of the prior art and (5) The level of predictability of the art:
While the state of the art is relatively high with regard to the treatment of specific tumor types with specific reagents, the state of the art with regard to treating tumor broadly is underdeveloped. In particular, there is no known anti-tumor agent that is effective against all tumor types. The tumor treatment art involves a very high level of unpredictability. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all tumors in a mammal with any combination of any type I IFNs and any ICIs (or PD-1 inhibitors or anti-PD1 antibodies) makes practicing the claimed invention unpredictable.
Tumors arising from different tissues differ in etiology and response to treatment. Heppner et al (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue, and tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult.
With regard to cancer treatment, Bally et al. (US 5,595,756) teaches although a number of bioactive agents have been found to be effective against tumor cells, the clinical use of such antitumor agents has been highly compromised because of treatment-limiting toxicities (Bally et al. col. 1, lines 17-24).
Sporn et al (“Chemoprevention of Cancer,” Carcinogenesis, Vol. 21 (2000), 525-530) teaches the magnitude of mortality of cancers and that new approaches to a variety of different cancer are critically needed. Sporn et al also teaches because the genotype and phenotype heterogeneity in advanced malignant lesions in individual patients, it is hard to know the specific molecular and cellular targets a potential therapy should target.
The effect of ICI, PD-1 inhibitor and PD-1 antibodies in cancer treatment is unpredictable. O’Neil and Cao teaches inhibition of the co-stimulatory protein of the immune checkpoint therapy is often associated with reduced immune response because T cells require co-stimulatory signals for its survival and activity. Amatore et al (Expert Opin. Ther. Targets 22:4, 343-351) teaches that ICOS (inducible T-cell costimulator, aka CD278) have both pro-tumoral and anti-tumoral role, and the choice of specific therapy would be based on immunological criteria such as whether ICOS is expressed mainly by tumor cells or by cytotoxic T cells (p.348, section 6 conclusion). If ICOS is mostly expressed in the T cells in a specific tumor type, an inhibitor is likely to promote the tumor growth (p.348, section 6 conclusion). Many small molecule inhibitors against PD-1/PD-L1 are being developed and tested, but the first oral PD-L1 inhibitor to enter clinical testing has been discontinued for toxicity reasons (News in Brief, “Oral PD-L1 inhibitors crowd into the clinic, Cancer Discov (2023) 13(1): OF2). Chen et al (Front. Immunol, 11:1088) teaches Despite PD-1 and PD-L1 inhibitors share the same function of blocking the PD-1/PD-L1 pathway, there is difference in the structure and clinical outcome, such as the clinical outcome between the two PD-1 antibodies, pembrolizumab and nivolumab. Similarly, Davar et al (J Clin Oncol. 2018 Oct 25; 36(35):3450-3458) and Atkins et al (Clin Cancer Res (2018) 24 (8):1805-1815) teaches administrating IFN-α and PD-1 antibody can have different clinical outcome in different cancer and patient population. Zhao et al (Ther Adv Med Oncol, 2020, 12:1-22) teaches the efficacies associated with PD-1/PD-L1 monotherapy vary significantly across cancer types and PD-L1 expression.
Furthermore, Sharma et al (Cell, 186 (8), 1652-1669), Zhao et al and Cristescu et al (JITC, 2022:10:e003091) teach there are other challenges for effective immune checkpoint therapy, such as resistance to the therapy, immune-related adverse events (irAEs), and significant variability in the effective of the therapy between patients due to high tumor mutational burden or PD-L1 expression.
In addition, Razaghi et al (Fron. Immunol. Volume 14-2023) teaches “the prospective effectiveness of a combined PD-1/PD-L1 blockade with type I IFN in cancer treatment depends on numerous factors including the type and dose of IFNa/b, the timing and duration of treatment, the tumor type and stage of cancer, the genetic and epigenetic alterations of tumor cells, the immune status of patients, and the interactions with other therapeutic interventions” (p.5, para.3).
Just like other types of cancers, the therapy against glioma is also highly unpredictable. Letchuman et al (Neurosurg Focus. 2022. 52(2): E5) teaches the effect of PD-1/PD-L1 inhibitors varies in different glioma mouse models (GL261, SB28 and CT-2A). Reardon et al (Cancer Immunol Res; 4(2) February 2016, refer to as Reardon 2016) teaches even in the same GL261-luc2 mouse model, different PD-1 inhibitors (anti-PD-1 antibody, anti-PD-L1 and anti-PD-L2 antibody) have variable outcomes.
Despite some success in some preclinical studies, the clinical trials testing PD-1 antibody monotherapy or in combination with other therapies in treatment of glioma have not shown success (Wang et al, Heliyou 10 (2024) e24729, section 1.10). This could be due to the fact that similar to other types of cancers, gliomas are heterogeneous at both the molecular and clinical level, and often requires different management and treatment strategies (Nabors et al, NCCN, Central Nervous system cancers, version 3. 2020). For instance, while nivolumab (PD-1 antibody) achieved durable responses in two siblings with bMMRD (biallelic mismatch repair deficiency) recurrent multifocal glioblastoma that had high tumor burden (Bouffet et al, J Clin Oncol. 2016. 34, 2206-2211), in a Phase 3 clinical trial, it only achieved the objective response rate of around 8% (7.8%; 95% CI, 4.1%-13.3%) in recurrent glioblastoma (Reardon et al, JAMA Oncology, 2020. 6(7): 1003-1010, refer to as Reardon 2020 thereafter).
Furthermore, the art indicates the difficulties in going from animal model to clinical studies for drug development for treatment of cancers. Gura T (Science, 1997, 278(5340): 1041-1042, encloses 1-5) indicates that the model systems used in cancer drug discovery are not predictive at all (see p. 1, 2nd paragraph). Gura T also teaches that the results of xenograft screening might not be much better than those obtained with the original models, mainly because the xenograft rumors do not behave like naturally occurring tumors in humans (see p. 2, 4th paragraph).
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “data suggest that the overall success rate for oncology products in clinical development is -10%” (see page 253, left column, the 1st paragraph). Hait further teaches several reasons why the outcome for a particular cancer target may be disappointing, such as incomplete understanding of the target in the pathogenesis of specific human malignancies, the putative role of cancer stem cells in limiting the efficacy of cancer therapeutics, the roles of single nucleotide polymorphisms in genes responsible for drug metabolism by affecting drug pharmacokinetics (page 253, Section “Understanding the target in context).
Hait also teaches drug effects in preclinical cancer models often do not predict clinical results. Despite several improvements have been made, including orthotopic implantation and use of mice with humanized hematopoietic and immune systems and newer genetic mouse models, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost (page 253, Section “Predictive models).
The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al (Chin Clin Oncol, 2014, 3(2):22, pages 1 -5). Gravanis et al. teaches the constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results, systemic biology approaches of the -omic type still generate largely incomprehensible, and animal models of cancer are similarly unable to predict the clinical situation (page 3, right column, the 2nd paragraph).
Given Bally et al. teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Amatore et al, Zhao et al, Chen et al, Razaghi et al, Sharma et al, Cristescue et al, Davar et al, and Atkins et al’s teaching of unpredictability of ICI, PD-1 inhibitor and PD-1 antibody in treatment of different types of cancers and patient population; Letchuman et al, Reardon 2016, Reardon 2020, Wang et al, Nabors et al and Bouffet et al’s teaching that different types of PD-1 inhibitors and PD-1 antibodies are unpredictable in glioma treatment in different patient population; Gura's teaching that the models are unpredictable; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; the cited references demonstrate that treatment of cancer using any type of IFN-α and any type of ICI (or PD-1 inhibitor or anti-PD1 antibody) is highly unpredictable.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples:
The instant specification is only enabling for one example of improving tumor sensitivity in a melanoma mouse model, by administration IFN-α and PD-1 blockade. Although the instant specification provides an example showing that type I IFN signaling is necessary to mediate the sensitivity of a GL-261 glioma to the anti-PD-1 mAb therapy (inst. Fig. 1, specs para. 6), it fails to show if the claimed method further would increase sensitivity of the glioma, such as in CT-2A model, which responds worse compared with GL261 model to PD-1 inhibitors (Letchuman et al, Neurosurg Focus. 2022. 52(2): E5). The specification is not enabling to use any types of type I IFN, any types of ICI (or any types of PD-1 inhibitor, or any types of anti-PD-1 antibody), to increase sensitivity of any types of tumors (or glioma) in any mammals.
Given the evidence above and the heterogeneity of tumors, unpredictable responsiveness to immune checkpoint therapeutics, PD-1 inhibitors and PD-1 antibodies, one of skill in the art could not reasonably extrapolate the findings for one specific method in a single specific type of cancer in mouse, to unlimited options of administering any type I IFN and any ICIs (of PD-1 inhibitors or PD-1 antibodies) in all of the hundreds of diverse benign tumors and cancers in all mammals (including different types of glioma), without undue experimentation.
In conclusion, the claimed invention does not provide enablement for the treatment of all tumors, including gliomas, with the recited method. Therefore, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claim Rejections - 35 USC § 102
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.
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.
Claims 1, 2, 4 and 7 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by patent publication CN 103536917 A to YANG Xuanming and FU Yangxin (referred as Yang hereinafter).
The claims are directed to a method of improving sensitivity of a tumor comprising administering a type I IFN and an ICI. The ICI is a PD-1 inhibitor in claim 2, which is any inhibitor of the PD-1/PD-L1/PD-L2 pathway as stated above. In claim 4, the tumor is refractory to immune checkpoint therapy prior to treatment. The type I IFN is administered to the subject via intratumoral injection.
Regarding claim 1, Yang teaches administering a type I IFN (IFN-ß) and an ICI (anti-PDL-1) reduces the tumor volume and achieves tumor free (example 7 and Fig. 7C) using a melanoma mouse model (B16-EGFR-SIY). Melanoma is a type of tumor and this model used (B16-EGFR-SIY) is resistant to anti-EGFR monotherapy (Para. 115) and responds poorly to anti-PDL-1 monotherapy (Fig. 7C). Administering IFN-ß and anti-PDL-1 together significantly reduces the tumor size compared with anti-PDL-1 monotherapy (para. 136 and Fig. 7C), increasing the sensitivity of the tumor. Therefore, Yang teaches the method of administering a type I IFN and an ICI increases the sensitivity of the tumor to a host immune response.
Regarding claim 2, Yang teaches the method uses an anti-PDL-1 (10F.9G2) (para.90 and Fig. 7C). As noted above, anti-PDL-1 is an example of PD-1 inhibitor since it’s an antibody blocking the PD-1/PD-L1 pathway as defined in the specification of the instant application (inst. specs. para. 19).
Regarding claim 4, Yang teaches the tumor is refractory to immune checkpoint therapy (responds poorly to anti-PD-L1 monotherapy) (Fig. 7C).
Regarding claim 7, Yang teaches the type I IFN is administered via intertumoral injection since the IFN-ß is linked to a targeting portion that binds to a tumor (anti-EGFR, para. 117 & 118, and Fig 7C) and the anti-EGFR-IFN-ß antibody is injected intratumorally (para.94).
Claims 1-4, 6-7, 9-11 and 13-14 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Liang et al (Nat Commun 9, 4586 (2018), referred as Liang hereafter).
The claims are directed to a method of improving sensitivity of a tumor comprising administering a type I IFN and an ICI. In claim 2, the ICI is a PD-1 inhibitor, which is any inhibitor of the PD-1/PD-L1/PD-L2 pathway as stated above. In claim 3, the ICI is an anti-PD-1 antibody. In claim 4, the tumor is refractory to immune checkpoint therapy prior to treatment. In claim 6, the type I IFN is an IFN-α. In Claim 7, the type I IFN is administered to the subject via intratumoral injection. In claim 9, the method comprises administering an anti-PD-1 antibody and a type I IFN, and the tumor was refractory to immune checkpoint therapy prior to treatment. In claim 10, the method comprises administering an anti-PD-1 antibody and IFN-α, and the tumor was refractory to immune checkpoint therapy prior to treatment. In Claim 11, the method comprises administering an anti-PD-1 antibody and IFN-α, the tumor was refractory to immune checkpoint therapy prior to treatment, and the IFN-α is administered via intratumoral injection. In claim 13, the method comprises administering an anti-PD-1 antibody and IFN-α. In claim 14, the method comprises administering an anti-PD-1 antibody and IFN-α, and the IFN-α is administered via intratumoral injection.
Regarding claims 1, Liang teaches the method of administering a type I IFN (IFN-α-Fc) increases the sensitivity of the tumor (overcome PD-L1 blockade resistance), and type I IFN (IFN-α-Fc) synergizes with the ICI (α-PD-L1), leading to increased sensitivity of tumors (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). Fc in IFN-α-Fc is reported to increase half-life of IFN-α in vivo and binding affinity (p. 2, right column, first para.).
Regarding claim 2, Liang teaches administering a type I IFN (IFN-α-Fc) and a PD-1 inhibitor (α-PD-L1), leading to increased sensitivity of tumors in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). In another example, Liang teaches administering a type I IFN (IFN-α-PD-L1) and a PD-1 inhibitor (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). In IFN-α-PD-L1, IFN-α is fused with the single-chain variable fragment of anti-PD-L1 antibody to target IFN-α into tumor (p. 2, 2nd para. and Fig. 2&3).
Regarding claim 3, Liang teaches administering a type I IFN (IFN-α-PD-L1) and an anti-PD1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b).
Regarding claim 4, Liang teaches administering a type I IFN (IFN-α-Fc) increases the sensitivity of the tumor (overcome PD-L1 blockade resistance), and type I IFN (IFN-α-Fc) synergizes with the ICI (α-PD-L1), leading to increased sensitivity of tumors (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance.
Regarding claim 6, Liang teaches the method of administering IFN-alpha (IFN-α-Fc) with an ICI (α-PD-L1) improves sensitivity of the tumor (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model, compared with anti-PD-L1 treatment alone and IFN-Fc treatment alone (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). Fc in IFN-α-Fc is reported to increase half-life of IFN-α in vivo and binding affinity (p. 2, right column, first para.).
Regarding claim 7, Liang teaches the type I IFN (IFN-α-Fc) synergizes with the ICI (α-PD-L1), increasing the sensitivity of tumors (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). Liang also teaches that this effect of IFN-α is dependent on intratumoral (i.t.) delivery of IFN-α (p.2 right col first para, also see Fig. 1d-e). In addition, Liang teaches systemic delivery (intravenous injection) of IFN-α could be accompanied with dose-limiting toxicities (p. 8 right col) and no treatment effect (p.2 right col first para, also see Fig. 1f).
Regarding claim 9, Liang teaches administering a type I IFN (IFN-α-PD-L1) and an anti-PD-1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance.
Regarding claim 10, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD-1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance.
Regarding claim 11, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD-1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance. Liang also teaches IFN-α-PD-L1 is a fusion protein of IFN-α with single-chain variable fragment of anti-PD-L1 antibody and it targets the IFN-α into tumor (p.2-3, section Construct armed PD-L1 antibody to deliver IFNα into tumor). In addition, Liang teaches systemic delivery (intravenous injection) of IFN-α could be accompanied with dose-limiting toxicities (p. 8 right col.).
Regarding claim 13, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b).
Regarding claim 14, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). Liang also teaches IFN-α-PD-L1 is a fusion protein of IFN-α with single-chain variable fragment of anti-PD-L1 antibody and it targets the IFN-α into tumor (p.2-3, section Construct armed PD-L1 antibody to deliver IFNα into tumor). In addition, Liang teaches systemic delivery (intravenous injection) of IFN-α could be accompanied with dose-limiting toxicities (p. 8 right col.).
Claim Rejections - 35 USC § 103
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.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-4 and 7-15 are rejected under 35 U.S.C. 103 as being unpatentable over Goldberg (US 20190083626 A1) in view of Liang et al (Nat Commun 9, 4586 (2018), referred as Liang hereafter)
The claims are directed to a method of improving sensitivity of a tumor comprising administering a type I IFN and an ICI. In claim 2, the ICI is a PD-1 inhibitor, which is any inhibitor of the PD-1/PD-L1/PD-L2 pathway as stated above. In claim 3, the ICI is an anti-PD-1 antibody. In claim 4, the tumor is refractory to immune checkpoint therapy prior to treatment. In claim 6, the type I IFN is an IFN-α. In Claim 7, the type I IFN is administered to the subject via intratumoral injection. In claim 8, the subject has undergone surgical resection of a tumor and the IFN-α is administered to the resection cavity. In claim 9, the method comprises administering an anti-PD-1 antibody and a type I IFN, and the tumor was refractory to immune checkpoint therapy prior to treatment. In claim 10, the method comprises administering an anti-PD-1 antibody and IFN-α, and the tumor was refractory to immune checkpoint therapy prior to treatment. In Claim 11, the method comprises administering an anti-PD-1 antibody and IFN-α, the tumor was refractory to immune checkpoint therapy prior to treatment, and the IFN-α is administered via intratumoral injection. In claim 12, the method comprises administering an anti-PD-1 antibody and IFN-α, the tumor was refractory to immune checkpoint therapy prior to treatment, and the IFN-α is administered to the resection cavity. In claim 13, the method comprises administering an anti-PD-1 antibody and IFN-α. In claim 14, the method comprises administering an anti-PD-1 antibody and IFN-α, and the IFN-α is administered via intratumoral injection. In claim 15, the method comprises administering an anti-PD-1 antibody and IFN-α, and the IFN-α is administered to the resection cavity.
Goldberg teaches by placing hydrogel that contains IFN-α, IFN-ß or anti-PD-1 antibody intraoperatively in the tumor resection cavity (tumor resection site) after the tumor resection in a mouse 4T1-Luc2 breast cancer model, tumor growth at the resection site and lung metastasis are inhibited, but the effect of anti-PD-1 antibody seems to be more variable compared with IFN-α or IFN-ß (para. 748, 779, 791-792 & 780, Fig. 49A, 70&71). In addition, Goldberg teaches a triple combination therapy (2’3-cGAMP, IL-15sa and anti-PD-1) eradicates the existing metastatic lesions and has durable survival benefit to a majority of mice compared with double therapies (para. 779-781, and Fig. 50-52), and an effective inducer of type I IFN is useful for this anti-tumor effect (para. 781). Goldberg also envisions the drug compositions delivered to the resection cavity can comprise a hydrogel, IFN-α and an anti-PD-1 antibody (para. 342). Hydrogel sustains the release of the small molecule and biologics in vivo, and itself has no effect on tumor growth (relapse) (example 5).
Goldberg fails to teach if administering both IFN-α and anti-PD-1 antibody would improve the sensitivity of a tumor to a host immune response, especially if the tumor is refractory to immune checkpoint therapy.
Regarding claims 1, Liang teaches the method of administering a type I IFN (IFN-α-Fc) increases the sensitivity of the tumor (overcome PD-L1 blockade resistance), and type I IFN (IFN-α-Fc) synergizes with the ICI (α-PD-L1), leading to increased sensitivity of tumors (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). Fc in IFN-α-Fc is reported to increase half-life of IFN-α in vivo and binding affinity (p. 2, right column, first para.).
Regarding claim 2, Liang teaches administering a type I IFN (IFN-α-Fc) and a PD-1 inhibitor (α-PD-L1), leading to increased sensitivity of tumors in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). In another example, Liang teaches administering a type I IFN (IFN-α-PD-L1) and a PD-1 inhibitor (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). In IFN-α-PD-L1, IFN-α is fused with the single-chain variable fragment of anti-PD-L1 antibody to target IFN-α into tumor (p. 2, 2nd para. and Fig. 2&3).
Regarding claim 3, Liang teaches administering a type I IFN (IFN-α-PD-L1) and an anti-PD1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b).
Regarding claim 4, Liang teaches administering a type I IFN (IFN-α-Fc) increases the sensitivity of the tumor (overcome PD-L1 blockade resistance), and type I IFN (IFN-α-Fc) synergizes with the ICI (α-PD-L1), leading to increased sensitivity of tumors (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance.
Regarding claim 6, Liang teaches the method of administering IFN-alpha (IFN-α-Fc) with an ICI (α-PD-L1) improves sensitivity of the tumor (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model, compared with anti-PD-L1 treatment alone and IFN-Fc treatment alone (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). Fc in IFN-α-Fc is reported to increase half-life of IFN-α in vivo and binding affinity (p. 2, right column, first para.).
Regarding claim 7, Liang teaches the type I IFN (IFN-α-Fc) synergizes with the ICI (α-PD-L1), increasing the sensitivity of tumors (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). Liang also teaches that this effect of IFN-α is dependent on intratumoral (i.t.) delivery of IFN-α (p.2 right col first para, also see Fig. 1d-e). In addition, Liang teaches systemic delivery (intravenous injection) of IFN-α could be accompanied with dose-limiting toxicities (p. 8 right col) and no treatment effect (p.2 right col first para, also see Fig. 1f).
Regarding claim 9, Liang teaches administering a type I IFN (IFN-α-PD-L1) and an anti-PD-1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance.
Regarding claim 10, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD-1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance.
Regarding claim 11, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD-1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance. Liang also teaches IFN-α-PD-L1 is a fusion protein of IFN-α with single-chain variable fragment of anti-PD-L1 antibody and it targets the IFN-α into tumor (p.2-3, section Construct armed PD-L1 antibody to deliver IFNα into tumor). In addition, Liang teaches systemic delivery (intravenous injection) of IFN-α could be accompanied with dose-limiting toxicities (p. 8 right col.).
Regarding claim 13, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b).
Regarding claim 14, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). Liang also teaches IFN-α-PD-L1 is a fusion protein of IFN-α with single-chain variable fragment of anti-PD-L1 antibody and it targets the IFN-α into tumor (p.2-3, section Construct armed PD-L1 antibody to deliver IFNα into tumor). In addition, Liang teaches systemic delivery (intravenous injection) of IFN-α could be accompanied with dose-limiting toxicities (p. 8 right col.).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to combine Goldberg’s method of administering IFN-α to the resection cavity to inhibit tumor growth and tumor metastasis, with Liang’s method of administering both IFN-α and anti-PD-1 antibody to a subject to increase the sensitivity of the tumor, to administer both IFN-α and anti-PD-1 antibody to a subject to increase the sensitivity of the tumor, with the IFN-α administered to the resection site, with a reasonable expectation of success. The motivation to do so is found in the teaching of Liang: administering both IFN-α (IFN-α-PD-L1) and anti-PD-1 antibody (α-PD-1) to a subject (mouse) increases the sensitivity of the tumor (reduces the tumor volume, reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, compared with anti-PD-1 antibody monotherapy and IFN-α monotherapy (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The advantages of increased tumor sensitivity when administering both IFN-α and anti-PD-1 antibody provides motivation to make the aforementioned combination with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1-7, 9-11, 13-14 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Tsugawa et al (Gene Therapy. 2004. volume 11, pages1551–1558), in view of Reardon et al (Cancer Immunol Res; 4(2) February 2016, refer to as Reardon 2016 thereafter) and Liang et al (Nat Commun 9, 4586 (2018), referred as Liang hereafter).
The claims are directed to a method of improving sensitivity of a tumor comprising administering a type I IFN and an ICI. In claim 3, the method comprises administering an anti-PD-1 antibody and a type I IFN. In claim 4, the tumor is refractory to immune checkpoint therapy prior to treatment. In claim 5, the tumor is glioma. In claim 6, the type I IFN is an IFN-α. In Claim 7, the type I IFN is administered to the subject via intratumoral injection. In claim 9, the method comprises administering an anti-PD-1 antibody and a type I IFN, and the tumor was refractory to immune checkpoint therapy prior to treatment. In claim 10, the method comprises administering an anti-PD-1 antibody and IFN-α, and the tumor was refractory to immune checkpoint therapy prior to treatment. In Claim 11, the method comprises administering an anti-PD-1 antibody and IFN-α, the tumor was refractory to immune checkpoint therapy prior to treatment, and the IFN-α is administered via intratumoral injection. In claim 13, the method comprises administering an anti-PD-1 antibody and IFN-α. In claim 14, the method comprises administering an anti-PD-1 antibody and IFN-α, and the IFN-α is administered via intratumoral injection. In claim 16, the method comprises administering an anti-PD-1 antibody and a type I IFN to improve sensitivity of glioma. In claim 17, the method comprises administering an anti-PD-1 antibody and a type I IFN to improve sensitivity of glioma that was refractory to immune checkpoint therapy prior to treatment. In claim 18, the method comprises administering an anti-PD-1 antibody and IFN-α to improve sensitivity of glioma that was refractory to immune checkpoint therapy prior to treatment. In claim 19, the method comprises administering an anti-PD-1 antibody and IFN-α to improve sensitivity of glioma.
Tsugawa et al teaches that administering IFN-α (Ad-IFN-α) intratumorally to a GL261 glioma model results in 23.5% of the mice surviving longer than 60 days (p.1552 right col., also Fig. 2a). Ad-IFN-α is an adenoviral vector (Ad) encoding mouse (IFN-α) gene (p.1556 left col. last para.). This increased survival rate is dependent on CD8+ cells and likely due to increased apoptotic glioma cell death (p.1552 section Results., also Fig. 1 and 2b). Therefore, Tsugawa teaches administering IFN-α (Ad-IFN-α) intratumorally to a GL261 glioma model increases the sensitivity of the glioma to a host immune response.
Tsugawa et al fails to teach if administering both IFN-α and an ICI (or a PD-1 inhibitor or an anti-PD-1 antibody) can increase the sensitivity of the glioma, especially if the glioma is refractory to immune checkpoint therapy prior to treatment.
Reardon 2016 teaches that administering anti-PD-1 antibody (blockade of PD-1) to mice bearing GL261-luc2 glioma (glioblastoma tumor) results in reduced tumor volume (tumor regression) and 56% of the mice surviving more than 140 days compared with controls (p. 126 section Eradicating established glioblastoma tumors and generating long-term survival). Reardon 2016 teaches that anti-PD-1 antibody increases the sensitivity of the tumor to anti-CTLA-4 monotherapy because by administering both anti-PD-1 and anti-CTLA-4 antibodies, the 75% of the mice survives more than 140 days compared with anti-CLTA-4 monotherapy (25%) (p. 126 section Eradicating established glioblastoma tumors and generating long-term survival, also Fig. 1B and tab. 1). Reardon 2016 also teaches that the tumor is refractory to immune checkpoint therapy because anti-PD-L2 (blockade of PD-L2) has no effect on mouse survival (p. 126 right col. para. 2-4).
Reardon 2016 fails to teach if administering both IFN-α and an ICI (or a PD-1 inhibitor or an anti-PD-1 antibody) can increase the sensitivity of the glioma, especially if the glioma is refractory to immune checkpoint therapy prior to treatment.
Regarding claims 1, Liang teaches the method of administering a type I IFN (IFN-α-Fc) increases the sensitivity of the tumor (overcome PD-L1 blockade resistance), and type I IFN (IFN-α-Fc) synergizes with the ICI (α-PD-L1), leading to increased sensitivity of tumors (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). Fc in IFN-α-Fc is reported to increase half-life of IFN-α in vivo and binding affinity (p. 2, right column, first para.).
Regarding claim 2, Liang teaches administering a type I IFN (IFN-α-Fc) and a PD-1 inhibitor (α-PD-L1), leading to increased sensitivity of tumors in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). In another example, Liang teaches administering a type I IFN (IFN-α-PD-L1) and a PD-1 inhibitor (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). In IFN-α-PD-L1, IFN-α is fused with the single-chain variable fragment of anti-PD-L1 antibody to target IFN-α into tumor (p. 2, 2nd para. and Fig. 2&3).
Regarding claim 3, Liang teaches administering a type I IFN (IFN-α-PD-L1) and an anti-PD1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b).
Regarding claim 4, Liang teaches administering a type I IFN (IFN-α-Fc) increases the sensitivity of the tumor (overcome PD-L1 blockade resistance), and type I IFN (IFN-α-Fc) synergizes with the ICI (α-PD-L1), leading to increased sensitivity of tumors (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance.
Regarding claim 6, Liang teaches the method of administering IFN-alpha (IFN-α-Fc) with an ICI (α-PD-L1) improves sensitivity of the tumor (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model, compared with anti-PD-L1 treatment alone and IFN-Fc treatment alone (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). Fc in IFN-α-Fc is reported to increase half-life of IFN-α in vivo and binding affinity (p. 2, right column, first para.).
Regarding claim 7, Liang teaches the type I IFN (IFN-α-Fc) synergizes with the ICI (α-PD-L1), increasing the sensitivity of tumors (reduced tumor volume) in A20 B-cell lymphoma mouse model and a MC38 colorectal cancer model (p.2 section IFNα delivered to tumor overcomes PD-L1 blockade resistance, also see Fig. 1d-e). Liang also teaches that this effect of IFN-α is dependent on intratumoral (i.t.) delivery of IFN-α (p.2 right col first para, also see Fig. 1d-e). In addition, Liang teaches systemic delivery (intravenous injection) of IFN-α could be accompanied with dose-limiting toxicities (p. 8 right col) and no treatment effect (p.2 right col first para, also see Fig. 1f).
Regarding claim 9, Liang teaches administering a type I IFN (IFN-α-PD-L1) and an anti-PD-1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance.
Regarding claim 10, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD-1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance.
Regarding claim 11, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD-1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The tumor is refractory to immune checkpoint therapy (has PD-L1 blockade resistance) and the method overcomes the resistance. Liang also teaches IFN-α-PD-L1 is a fusion protein of IFN-α with single-chain variable fragment of anti-PD-L1 antibody and it targets the IFN-α into tumor (p.2-3, section Construct armed PD-L1 antibody to deliver IFNα into tumor). In addition, Liang teaches systemic delivery (intravenous injection) of IFN-α could be accompanied with dose-limiting toxicities (p. 8 right col.).
Regarding claim 13, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b).
Regarding claim 14, Liang teaches administering IFN-alpha (IFN-α-PD-L1) and an anti-PD1 antibody (α-PD-1) increases sensitivity of the tumor (reverse tumor resistance to PD-1 blockade) in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model, and the combination therapy (administering both IFNα-PD-L1 and α-PD-1) lead to better tumor control (reduced tumor volume) (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). Liang also teaches IFN-α-PD-L1 is a fusion protein of IFN-α with single-chain variable fragment of anti-PD-L1 antibody and it targets the IFN-α into tumor (p.2-3, section Construct armed PD-L1 antibody to deliver IFNα into tumor). In addition, Liang teaches systemic delivery (intravenous injection) of IFN-α could be accompanied with dose-limiting toxicities (p. 8 right col.).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to combine Tsugawa et al’s method of administering IFN-α to increase sensitivity of glioma, Reardon 2016’s method of administering anti-PD-1 antibody to increase sensitivity of glioma, and Liang’s method of administering both IFN-α and anti-PD-1 antibody to increase sensitivity of a tumor, to administering both IFN-α and anti-PD1 antibody to increase the sensitivity of a glioma, with a reasonable expectation of success. The motivation is in the teaching of Liang: administering both IFN-α (IFN-α-PD-L1) and anti-PD-1 antibody (α-PD-1) to a subject (mouse) increases the sensitivity of the tumor (reduces the tumor volume, reverse tumor resistance to PD-1 blockade), compared with anti-PD-1 antibody monotherapy and IFN-α monotherapy in an advanced A20 B-cell lymphoma mouse model and a B16 melanoma mouse model (p.5-6, section IFNα-anti-PD-L1 reverses tumor resistance to PD-1 blockade, and Fig. 6a-b). The advantages of increased tumor sensitivity when administering both IFN-α and anti-PD-1 antibody provides motivation to make the aforementioned combination with a reasonable expectation of success.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Conclusion
All claims are rejected.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Hardcastle et al (Neuro-Oncology, Volume 19, Issue 4, 1 April 2017, Pages 493–502) teaches administering PD-1 antibody (αPD-1) to mice bearing GL261 glioma is able to improve the mouse survival compared with untreated control (Fig. 3A).
Bouard et al (Human Gene Therapy. June 2003.14: 883-895) teaches IFN-α expression is able to inhibit tumor growth in a rat 9L gliosarcoma model, compared with rats implanted with non-transduced cells or cells expressing angiostatin (Fig. 4A and 7), thereby increasing the sensitivity of the glioma.
Son et al (Int J Oncol. 2006 Jun;28(6):1385-92) teaches administering IFN-α (pegylated IFN-α-2b) reduces the number of proliferating tumor cell proliferation in mouse glioma (U-87MG glioblastoma) model (p. 1387-1388 section Determination of the optimal biological schedule of PEG-IFN-α, also see Fig. 3). Son et al also teaches that IFN-α (PEG-IFN-α) synergizes with paclitaxel to further reduces the tumor volume (p.1389-1390 section Synergistic therapy of PEG-IFN-α and paclitaxel, also see Fig. 5). PEG-IFN-α is a potent, long-lasting form of IFN-α designed to enhance its pharmacokinetic characteristics and reduce immunogenicity (p.1385 last line to p.1386 l.2).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIAN YANG whose telephone number is (571)272-6204. The examiner can normally be reached Monday - Thursday 8:00 am - 4:30 pm, Friday 8:00 am - 2:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIAN YANG/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674