DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/23/2026 has been entered.
Claim 26 is amended and claims 1-25 and 27 are cancelled. Claims 26 and 28-48 are currently pending and are examined on the merits herein.
Priority
The instant application, filed 12/17/2021, is a 371 filing of PCT/US2019/040964, filed 07/09/2019, and claims foreign priority to PCT/US2019/037978, filed 06/19/2019.
Withdrawn Objections and Rejections
In the office action of 09/23/2025, claim 27 was rejected under 35 USC 103 and on the grounds of nonstatutory double patenting. The cancellation of the claim has rendered the rejections moot and the rejections are withdrawn.
The claims were rejected on the grounds of nonstatutory double patenting over US 11,583,593. The rejections are withdrawn in favor of the modified rejections below.
The following grounds of rejections are modified.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 26, 28-29, 31, 32, 37-39, 41-44, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012 in view of US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018 and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739.
US’016 teaches pharmaceutical compositions containing tumor-selective targeted inhibitor glycoconjugates. The conjugates comprise ALK5 inhibitors covalently bound to biocompatible carrier molecules which selectively target and specifically bind to Muc4. The ALK5 inhibitors are conjugated to tumor targetable glycans with an acid labile linker. The linkers are designed to be stable in plasma and release pharmacologically active inhibitors through acid-catalyzed hydrolysis in the acidic environment of the target tumor where the inhibitor activity is restored. Because the glycoconjugates are stable at physiological pH and in plasma, they advantageously reduce undesirable systemic ALK5 inhibitor activity (abstract). US’016 further teaches that ALK5 inhibitors inhibit TGF-β signaling (page 2, [0008]).
US’016 teaches a method for treating a subject having cancer comprising administering to the subject an ALK5 inhibitor-conjugate in an effective amount (page 14, [0362]).
US’016 teaches that the acid-liable linker is a hydrazone-based linker, a carbohydrazide-based linker, a sulfohydraine-based linker, or a dihydrazine-based linker (page 13, [0359]).
US’016 further teaches that the ALK5 inhibitor can be a pyrazole type ALK5 inhibitor (pages 4-5, [0021]), and provides species of such compounds including: dimethyl-{ 2-[( 4-{ 4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]-2-pyridinyl }phenyl)oxy]ethyl}amine (page 7, [0092]), which has the structure shown below:
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The compound shown above, disclosed by US’016, differs from the first and second structures of the instant claims (and those of instant claims 28 and 29) in that the compound of US’016 has two methyl groups on the alkylamine moiety. The structure also differs from the 2nd of the instantly claimed structures (and that of instant claim 29) in that it is missing the methyl group on the left pyridine group.
These substitutions/additions; however, would have been obvious in view of the teachings of US’016.
US’016 teaches structures for pyrazole type ALK5 inhibitors with the following genus (pages 4-5, [0021]):
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US’016 teaches that R4 has a structure of
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US’016 teaches that A can be a direct bond or an alkyl having from 1 to 5 carbon atoms, and R6 can be pyrole, cyclohexyl, morpholino, pyrazole, pyran, imidazole, oxane, pyrrolidinyl, or alkylamine (page 5, [0022]). In the structure of US’016, [0092], which is shown above, A is an alkyl group having 2 carbon atoms and R6 is a species of alkylamine (with two carbons). US’016 further teaches that, in accordance with the disclosure, the term alkyl refers to a branched or straight chain acyclic group comprising one to ten carbon atoms (page 12, [0346]). As US’016 teaches that R6 can be any alkylamine, and that alkyl indicates 1-10 carbon atoms, an ordinarily skilled artisan would reasonably envision the methylamine group of the instantly claimed compounds.
US’016 further teaches that R2 is hydrogen, halogen, or lower alkyl having from 1 to about 5 carbon atoms.
The teachings of US’016 differ from the instantly claimed invention in that US’016 does not disclose that the targeting moiety in the conjugate is an antibody or an antigen binding fragment that binds to a T cell surface molecule or the combination of the conjugate with a checkpoint inhibitor.
US’569 teaches anti-PD-1 antibodies and uses thereof in treating diseases associated with PD-1 signaling, such as cancer (abstract). PD-1, also known as CD279, is a cell surface receptor expressed on immune cells including T cells. PD-1 binds to two ligands, PD-L1 and PD-L2 and this binding triggers the PD-1 mediated signaling pathway, which is believed to negatively regulate immune responses. PD-1 is an immunoglobulin (Ig) superfamily member which includes CD28 and CTLA-4. PD-1 and other family members are type I transmembrane glycoproteins containing extracellular Ig domains responsible for binding (page 1, [0002]). Tumors evade immune surveillance by creating an immune suppressive microenvironment. Expression of PD-1 and PD-L1 on tumor infiltrating lymphocytes or tumor cells has been found in a number of primary tumor biopsies and is known to contribute to the immune evasion. Such tissues include cancers of the lung, liver, ovary, cervix, skin, colon, glioma, bladder, breast, kidney, esophagus, stomach, oral squamous cell, urothelial cell, and pancreas, as well as tumors of the head and neck (page 1, [0004]). Blockade of the interactions between PD-1 and its ligands enhances tumor specific CD8 T cell immunity that is capable of eliminating tumor cells (page 1, [0005]).
US’569 teaches that an anti-PD-1 antibody is an immunoglobulin molecule capable of specific binding to a PD-1 protein or a fragment thereof through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. The term “antibody” encompasses not only intact (i.e., full-length) polyclonal or monoclonal antibodies, but also antigen-binding fragments (page 3, [0058]). The antibodies can be monoclonal antibodies (page 4, [0060]). The antibodies can also be human or humanized antibodies (page 3, [0059]).
US’569 teaches that the anti-PD-1 antibody can be conjugated with a suitable agent, such as a therapeutic agent, to form a conjugate, e.g., an antibody drug conjugate (ADC) (page 2, [0012]). For instance, the anti-PD-1 antibody disclosed is linked to a cytotoxic agent, a radioisotope, or a drug. Methods of making such an immunoconjugate are well known in the art. For example, the antibody may be modified with a bifunctional agent to induce an active disulfide moiety. If needed, the agent to be conjugated to the antibody may be modified to introduce a thiol-group following routine practice. Reaction of the thiol-containing agent would produce an immunoconjugate in which the antibody and the agent are linked via disulfide bonds (page 7, [0088]).
US’569 further teaches that the anti-PD-1 therapies disclosed can be administered with a suitable second agent. Examples of suitable second agents for co-use with the antibodies include an antibody binding to a co-stimulatory receptor, for example CD137/4-1BB, OX40, CD40, ICOS, CD27, HVEM, or GITR; an agent that induces immunogenic cell death; an agent that inhibits a checkpoint molecule, for example CTLA4, LAG3, TIM3, B7H3, B7H4, BTLA, or TIGIT; an agent that modifies an immunosuppressive enzyme, or an agent that modulates myeloid cells (page 10, [0116]).
US’569 compares a disclosed antibody with commercially purchased antibody Opdivo, which is nivolumab (page 14, [0150]).
Yoon teaches that a variety of TGF-β antagonists have been developed to intervene with excessive TGF-β signaling activity in cancer. ALK5 inhibitors antagonize TGF-β signaling by blocking TGF-β receptor-activated Smad (R-Smad) phosphorylation (abstract). TGF-β is the most potent immunosuppressive cytokine and is abundantly produced and activated in the tumor microenvironment. TGF-β suppresses anti-tumor immunity by direct inhibiting and the differentiation and functions of various effector cells, such as NK cells, Th1 cells, and cytotoxic T lymphocytes (CTL). In addition to direct immune suppression, TGF-β indirectly suppresses anti-tumor immunity by inducing suppressor immune cell subsets including Tregs and myeloid derived suppressor cells (page 1721, left column, paragraph 1).
Yoon studied the mechanisms of how ALK5 inhibitors exert a therapeutic effect using a mouse model of melanoma (abstract). Melanoma is a prototypical immunogenic tumor expressing melanoma associated antigens, which are targeted by CTLs. Intensive efforts have focused on developing immunotherapies to activate anti-melanoma T-cell responses. However, melanoma cells produce high amounts of TGF-β, which limit the success of immunotherapy by rendering the host immune response tolerant to tumor-associated antigens (page 1721, left column, paragraph 2). In the study provided, the cellular and molecular mechanisms of EW-7197 (an orally available ALK5 inhibitor) and a representative inhibitor, LY-2157299, was studied (paragraph bridging page 1721).
Yoon teaches that the ALK5 inhibitors suppressed the progression of melanoma with enhanced cytotoxic T-lymphocyte (CTL) responses. Notably, ALK5 inhibitors not only blocked R-Smad phosphorylation, but also induced ubiquitin-mediated degradation of the common Smad, Smad4, mainly in CD8+ T cells in melanoma bearing mice. Accordingly, T-cell specific deletion of Smad4 was sufficient to suppress the progression of melanoma. Eomes, the T-box transcription factor regulating CTL functions, was further identified as a specific target repressed by TGF-β via Smad4 and Smad3 in CD8+ T cells. Thus, ALK5 inhibition enhances anti-melanoma CTL responses through ubiquitin-mediated degradation of Smad4 in addition to the direct inhibitory effect on R-Smad phosphorylation (abstract).
Yoon teaches that TGF-β and EW-7197 showed no direct effects on cell apoptosis and the cell cycle of B16 (melanoma) cells in vitro indicating that TGF-β antagonism mainly targets the immune system rather than the cancer cells. Treatment with EW-7197 increased the proportions and numbers of CD8+ T cells significantly in the dLNs, non dLNs, and spleens. Furthermore, CD8+ T cells from EW-7197 treated mice induced significantly more apoptosis of target B16 cells (page 1721, right column, paragraph 3).
Yoon reports similar findings in a mouse 4T1 model of metastatic breast cancer, teaching that treatment with the ALK5 inhibitor resulted in a significant increase in CD8+ T cells with upregulated Eomes expression in CD4+ deleted and NK-deleted mice as well as controls. Yoon teaches that the data is in line with previous reports that the anti-tumor effect of TGF-β antagonism mainly depends on CD8+ T cells (page 1726, right column, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the species of ALK5 inhibitor disclosed by US’016, [0092], by substituting the dimethylamine group with an alternative alkylamine, including methylamine, and to additionally substitute the hydrogen group on the left pyridine group with a methyl group based on the genus structures disclosed by US’016. It would have further been obvious to substitute the MUC4 targeting moiety in the ALK5 drug conjugate taught by US’016 with the anti-PD-1 antibody or antigen binding fragment taught by US’569 based on the teachings of Yoon. It would have further been obvious to administer the conjugate in combination with a checkpoint inhibitor based on the teachings of US’569.
It would have been obvious to substitute the dimethylamine group in the ALK5 inhibitor disclosed by US’016, [0092] with a methylamine as US’016 teaches that the moiety in that position on the inhibitor can be an alkylamine and further teaches that alkyl indicates one to ten carbon atoms, indicating that an alkylamine with one to ten carbon atoms could be used and would be reasonably expected to have analogous properties. Additionally, it would have been obvious to substitute the hydrogen on the left pyridine group with a methyl group as US’016 teaches these groups as alternatives for the R4 position providing a reasonable expectation that the compounds would have analogous properties. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
An ordinarily skilled artisan would have been motivated to substitute the targeting moiety with an antibody or antigen binding fragment that targets T cells, such as the anti-PD-1 antibody of US’569, as Yoon demonstrates that ALK5 inhibitors induce ubiquitin-mediated degradation of Semad4 in CD8+ T cells in addition to the direct inhibition of R-Smad phosphorylation leading to enhanced CTL responses through depression of Eomes. Additionally, Yoon teaches that the anti-tumor effects of ALK5 inhibitors mainly depend on CD8+ T cells and that such antagonists effect the immune system. An ordinarily skilled artisan would have had a reasonable expectation of success as US’569 teaches that the anti-PD-1 antibody can be used in antibody drug conjugates and that methods of making such conjugates were known in the art. Additionally, all of US’016, US’569, and Yoon teach and study methods of treating cancer.
It would have further been obvious to administer the conjugate in combination with a checkpoint inhibitor, such as those disclosed by US’569, as US’569 teaches the targeting of the checkpoints in combination with anti-PD-1 antibody conjugates for modulation of the tumor immunosuppressive microenvironment.
Claims 33-36 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012 in view of US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018 and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739 as applied to claims 26 and 31 above, and in further view of McCombs, J.R. and S.C. Owens (2015) Antibody drug conjugates: design and selection of linker, payload, and conjugation chemistry The AAPS Journal 17(2); 339-351.
The combination of US’016, US’569, and Yoon teach the method of claim 31 as discussed in detail above.
As discussed above, US’016 teaches that the acid-liable linker is a hydrazone-based linker.
The combination of applied references, however, does not disclose that the cleavable linker is as recited in claims 33-36.
McCombs teaches that ADCs have emerged as an important class of drugs designed to harness the specificity of antibodies with the potency of small molecule therapies. The three main components of ADCs are the antibody, the linker and the payload. McCombs reviews popular conjugations methods including the contrasting characteristics of cleavable and non-cleavable linkers (abstract).
McCombs teaches that cleavable linkers are popular in the ADC clinical pipeline with acid-sensitive linkers such as hydrazones and silyl ethers at the forefront. Hydrazones are easily synthesized and have a plasma half-life of 183 h at pH 7 and 4.4 h at pH 5, suggesting that they are selectively cleavable under acidic conditions, such as those found in the lysosome (page 345, left column, paragraph 1).
McCombs further teaches that enzymatically cleavable linkers are gaining significant attention in ADC development due to superior plasma stability and release mechanism. The most popular enzymatic cleavage sequence is the dipeptide valine-citrulline, combined with a self-immolative linker p-aminobenzyl alcohol (PAB). Cleavage of the amide-linked PAB triggers a 1,6-elimination of carbon dioxide and concomitant release of the free drug in parent amine form (page 346, left column, paragraph 2; page 345, Figure 8C).
McCombs teaches that, in a study comparing the potency of MMAE linked by dipeptide linkers including Val-Cit, the Val-Cit linker proved to be over 100 times as stable as the hydrazone linker in human plasma (page 346, left column, paragraph 4).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the hydrazone cleavable linker in the ALK5 conjugate taught by the combination of US’016, US’569, and Yoon with the enzymatically cleavable dipeptide linker valine-citrulline as taught by McCombs. An ordinarily skilled artisan would have been motivated to make this substitution as McCombs teaches that the Val-Cit linker was shown to be over 100 times as stable in plasma as a hydrazone linker when tested in an ADC. An ordinarily skilled artisan would have had a reasonable expectation of success as McCombs provides alternatives to the cleavable hydrazone linker for use in drug conjugates.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012 in view of US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018 and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739 as applied to claim 26 above, and in further view of Consuegra-Fernandez, M., et al (2015) CD5 as a target for immune-based therapies Clinical Reviews in Immunology 32(2); 85-115.
The combination of US’016, US’569, and Yoon teach the method of claim 26 as discussed in detail above.
The combination of applied references, however, does not disclose that the T cell surface molecule is CD5.
Consuegra-Fernandez teaches that CD5 was one of the first surface receptors described for mouse and human T lymphocytes and is positioned as an attractive target for developing immunotherapies aimed at either boosting or dampening an ongoing immune response. Consuegra-Fernandez reviews the function of CD5 and its involvement in the regulation of immune responses in health and disease, and provides discussion regarding the development of therapeutic strategies aimed at targeting CD5 for autoimmune diseases, cancer, and infections (abstract).
CD5 is a highly specific lymphoid marker expressed by all mature T cells and is directly proportional to the avidity of the TCR-ligand interaction. In general, the expression levels found in peripheral T cells are the highest in CD4+TCRαβ cells followed by CD8+TCRαβ cells and then CD4-CD8-TCRγδ cells (page 88, left column, paragraph 1).
Consuegra-Fernandez teaches that, in cancer, the destruction of tumor cells by the immune system is controlled by receptors that tightly regulate, positively or negatively, T-cell effector functions. Some current immunotherapeutic strategies in cancer are based on blocking the inhibitory receptor for B7, CTLA-4, whose role it is to shut off responses against self-antigens. Very encouraging results were recently obtained in patients with different types of tumors by blocking another inhibitory receptor, PD-1, which prevents T-cell activation. Along this line, CD5 also behaves as a negative modulator of activation and differentiation signals mediated by the T-cell receptor, and has been shown to contribute to the regulation of antitumor immune responses. An early study in mice reported that nondepleting mAb against CD5 was efficacious in the treatment of lymphoid (EL-4 leukemia) and nonlymphoid (Lewis lung carcinoma) tumors (page 100, right column, paragraphs 2-3, D. Cancer).
Consuegra-Fernandez teaches that targeting of new immunological checkpoints such as CTLA-4 and PD-1/PD-L1 in cancer has yielded promising results in clinical trials, especially in patients with metastatic melanoma. The available data suggests that CD5 represents a new checkpoint molecule, opening up new therapeutic possibilities based on neutralizing anti-CD5 mAbs alone or in combination with other therapies (page 101, left column, paragraph 3).
Consuegra-Fernandez also teaches that there had been pilot studies in human SLE patients using an immunoconjugate composed of a murine anti-CD5 mAb bound to a ricin toxin (page 94, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the ALK5 antibody drug conjugate taught by the combination of US’016, US’569, and Yoon to target CD5, using an anti-CD5 antibody, in place of PD-1 based on the teachings of Consuegra-Fernandez. It would have been obvious to target CD5 in place of PD-1 as Consuegra-Fernandez teaches that CD5 is a surface receptor that is found on human T lymphocytes and is positioned as an attractive target for immunotherapies. Additionally, Consuegra-Fernandez teaches that the targeting of CD5 can be used as a means of modulating immune response by targeting T cells and compares CD5 to PD-1 and CTLA-4. An ordinarily skilled artisan would have had a reasonable expectation of success as Consuegra-Fernandez teaches the targeting of CD5 for cancer treatment and also teaches prior development of ADCs targeting CD5 for targeted delivery of drugs.
Claims 43-47 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012 in view of US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018 and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739 as applied to claim 26 above, and in further view of Holmgaard, R.B., et al (2018) Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as a monotherapy and in combination with checkpoint blockade Journal for ImmunoTherapy of Cancer 6(47); 1-15.
The combination of US’016, US’569, and Yoon teach the method of claim 26 as discussed in detail above.
The combination of applied references, however, does not disclose that the checkpoint inhibitor targets PD-1 as recited in claim 45 and is selected from those recited in claims 46-47.
Holmgaard teaches that TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion, and metastasis, and escape from immune surveillance (abstract, background). Holmgaard teaches that clinical studies have provided proof of concept data supporting the role of TGFβ in cancer and the utility of targeting the TGFβ pathway. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of TGFβ receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Holmgaard teaches that Galunisertib was currently under clinical development in combination with checkpoint inhibitors, including nivolumab and durvalumab, in patients with NSCLC, HCC, or pancreatic cancer (page 2, right column, paragraph 3).
Holmgaard teaches that Galunisertib enhances the development of anti-tumor T cell immunity through modulating both effector and regulatory T cell function. Using a breast cancer model, it is shown that Galunisertib mediates robust anti-tumor T cell immunity and promotes the establishment of T cell memory and antigen spreading. Using in vitro assays and primary human Treg cells, it is shown that Galunisertib treatment blocks the suppressive activity of human Tregs, further highlighting its role in T cell immunity. The TGFβ pathway was recently described as a potential mechanism of resistance for anti-PD-1/PD-L1 checkpoint blockade. To this end, it is shown that Galunisertib treatment at a clinically relevant dose enhances the anti-tumor activity of anti-PD-L1, resulting in robust tumor regressions associated with enhanced T-cell activation signatures, further supporting the clinical development of TGFβRI in combination with checkpoint blockade (paragraph bridging pages 2-3).
Holmgaard teaches that the results provided suggest at least an additive activity with potential of synergy when targeting both the TGFβ and PD-1 pathways. Additionally, the anti-tumor activity of Galunisertib was tested in a broad range of murine tumor models with similar results, further suggesting that the TGFβ inhibition is immune mediated and thus not restricted to specific tumor indications (page 13, right column, paragraph 1).
Holmgaard concludes that the data provides a strong rationale to clinically explore the potential of Galunisertib to enhance anti-tumor immune response, particularly in combination with PD-1/PD-L1 checkpoint inhibitors (page 14, left column, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of US’016, US’569, and Yoon to use an anti-PD-1/PD-L1 antibody, such as nivolumab or durvalumab, as the checkpoint inhibitor based on the teachings of Holmgaard. An ordinarily skilled artisan would have been motivated to administer the ADC with an anti-PD-1/PD-L1 antibody, such as nivolumab or durvalumab, as Holmgaard teaches that preclinical results suggest the potential for synergy when the TGFβ and PD-1 pathways are targeted in combination. Additionally, Holmgaard teaches that the combination of Galunisertib (LY2157299 monohydrate) was currently under clinical development in combination with checkpoint inhibitors including nivolumab and durvalumab. An ordinarily skilled artisan would have had a reasonable expectation of success as the ADC taught by the combination of US’016, US’569, and Yoon includes an ALK5 inhibitor, which both US’016 and Yoon teach antagonizes the TGFβ pathway. Additionally, Yoon uses LY-2157299 as a comparison to an ALK5 inhibitor, demonstrating that both function in blocking the TGFβ pathway and enhancing T cell immunity.
Response to Arguments
Applicant’s arguments in the response filed 03/23/2026 has been fully considered in so far as they apply to the rejections of the instant office action, but are not persuasive.
It is noted that the rejection has been modified and now references the compound recited in paragraph [0092] of US’016 in place of the previously referenced compound recited in paragraph [0130]; however, applicant’s arguments still apply.
With regards to the rejections under 35 USC 103, applicant argues that the rejection does not explain why one of ordinary skill in the art would have chosen the specifically referenced compound of US’016 as the lead compound. Applicant argues that US’016 does not disclose any activity data for the compound and that selection of the compound is based on hindsight benefit. Applicant cites MPEP 2143(I)(B) for support.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Although US’016 did not test or provide activity data for the compounds disclosed, US’016 teaches genus structures as well as a finite number of species of ALK5 inhibitors. Based on the disclosure of US’016, one of ordinary skill in the art would have reasonably arrived at the instantly claimed invention with a reasonable expectation of success. As discussed in detail in the rejections of the instant office action, US’016 teaches an ALK5 inhibitor that is identical to that of the first compound of instant claim 26 with the exception of a dimethylamine when the instantly claimed compound comprises a methylamine. US’016; however, teaches that the moiety in this position may be from the alkylamine genus and also teaches that alkyl, as referenced in the disclosure, references one to ten carbon atoms. As such, one of ordinary skill in the art would have reasonably envisioned the claimed compound. Additionally, as US’016 teaches that the moiety may be from the genus of alkylamine, an ordinarily skilled artisan would have expected analogous properties if the dimethylamine was substituted with an alternative alkylamine, including methylamine.
MPEP 2143, cited by applicant in the response, provides Examples 8-11 all of which discuss lead compounds. Example 9 states “The Federal Circuit in Eisai makes it clear that from the perspective of the law of obviousness, any known compound might possibly serve as a lead compound.” The example further indicates that the term “lead compound” can have a contextual meaning that may vary from the way a pharmaceutical chemist might use the term. Therefore, while US’016 does not provide activity data for the compounds, one of ordinary skill in the art would have still reasonably arrived at the instantly claimed compound with a reasonable expectation that the compound would have analogous properties to the species disclosed by US’016.
It is further noted that KSR(B) does not require explicit motivation in the art in order to arrive at a prima facie case of obviousness. Rather, KSR(B) requires a finding that the art contained a method or product that differed from the instantly claimed compound by the substitution of one component with another component; a finding that the substitute components were known in the art; and a finding that one of ordinary skill in the art could have substituted one known element for another and that the substitution would have been predictable. MPEP 2143 B, Example 11 states “the Federal Circuit stated that a "restrictive view of the lead compound test would present a rigid test similar to the teaching-suggestion-motivation test that the Supreme Court explicitly rejected in KSR”.
Applicant further argues that the genus compounds referenced in the rejection do not encompass the selected lead compound and that the office action does not explain why one of ordinary skill in the art would modify the compound of US’016, [0092] based on the features from a different genera. Applicant specifically points to the five membered ring with a single nitrogen atom compared to the species compound which has an additional nitrogen atom. Applicant argues that the genus that has two nitrogen atoms in the five membered ring has an unsubstituted 4-pyridinyl group.
While applicant argues that the genus has only a single nitrogen atom in the five membered ring, as opposed to two as are present in the species of US’016, [0092], and that the other genus which does have two nitrogen atoms has an unsubstituted 4-pyridinyl group, it is considered that both are pyrazole type ALK5 inhibitors with the same ring structures. Additionally, it is clear from the disclosure of US’016 that two nitrogen atoms in the five membered ring structure with a substituted 4-pyridinyl group had been considered. For instance, one of the two pyrazole like genus discussed by applicant has two nitrogen as does the species referenced in the rejection which also has a moiety attached to the 4-pyridinyl group. US’016 also refers to the compounds as pyrazole type inhibitors, which is indicative of two adjacent nitrogen atoms on a five member ring. US’016 considers that a moiety in the same position on a pyrazole inhibitor with the same general ring structures can be an alkylamine which suggests that any alkylamine used in the position would have analogous properties. Applicant does not provide any evidence to suggest that the modifications proposed would not have been predictable or that the claimed compounds provide any unexpected property or result compared to that disclosed by US’016.
Applicant further argues that the compound recited in claim 29 has been found by the office to be nonobvious and patentable, referencing claim 1 of US patent 11,987,558. Applicant argues that US’016 was cited during prosecution of the ‘558 patent as indicated by the front page and that by asserting that the compound would have been obvious in view of US’016 is thus indirectly expressing an opinion on the patentability of the issued claim to the compound contrary to MPEP 1701.
It is first noted that at no point does the rejection of the instant office action, or any other preceding office action, provide opinion as to the validity or invalidity of, or the patentability or unpatentability of any claim in any U.S. patent. Furthermore, patentability is assessed based on the current claims in the present application and is done so on an individual basis.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 11,583,593 B2
Claims 26, 28-29, 31-39, 41-44, and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,583,593 in view of US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018, US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012, and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739.
US’593 claims a composition comprising an ALK5 inhibitor covalently attached to a protease-sensitive linker wherein the ALK5 has the structure shown below:
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The claimed structure is identical to that of the 2nd compound in instant claim 26 and the compound of instant claim 29.
US’593 further claims that the protease-sensitive linker is a dipeptide, tripeptide, tetrapeptide, or a pentapeptide (claim 2), and comprises a valine-citrulline dipeptide (claim 3).
The claims of US’593 differ from the instant claims in that the claims of US’593 do not claim that the compound is linked to an antibody or antigen binding fragment that binds to a T cell surface molecule. US’593 also does not claim the use of the conjugate in a method of treating cancer and used in combination with a checkpoint inhibitor.
The teachings of US’569, US’016, and Yoon are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to conjugate the ALK5 inhibitor and linker claimed in US’593 to an anti-PD-1 antibody or antibody fragment, such as that taught by US’569, as supported by US’016, and to have administered the conjugate in a method of treating cancer based on the teachings of Yoon. It would have further been obvious to coadminister a checkpoint inhibitor based on the teachings of US’569. An ordinarily skilled artisan would have been motivated to add a targeting moiety that targets T cells, such as the anti-PD-1 antibody, as Yoon demonstrates that ALK5 inhibitors induce ubiquitin-mediated degradation of Semad4 in CD8+ T cells in addition to the direct inhibition of R-Smad phosphorylation leading to enhanced CTL responses through depression of Eomes. Additionally, Yoon teaches that the anti-tumor effects of the inhibitors mainly depend on CD8+ T cells and that response to such antagonism targets the immune system rather than the cancer cells. An ordinarily skilled artisan would have had a reasonable expectation of success as US’569 teaches that the anti-PD-1 antibody can be used in antibody drug conjugates and that methods of making such conjugates were known in the art. The conjugation of the ALK5 inhibitor is further supported by US’016, which demonstrates that the art had considered conjugates comprising ALK5 and targeting moieties in the treatment of cancer. It would have further been obvious to administer the conjugate in combination with a checkpoint inhibitor, such as those disclosed by US’569, as US’569 teaches the targeting of the checkpoints in combination with anti-PD-1 antibody conjugates for modulation of the tumor immunosuppressive microenvironment.
Regarding claim 28, the structure claimed in US’593 differs from the instantly claimed compound in the addition of a methyl group on the pyridine group.
As discussed above, US’016 teaches a genus in which the R2 group is hydrogen or an alkyl having 1 to 5 carbon atoms.
It would have been prima facie obvious to one of ordinary skill in the art to substitute the methyl group in the ALK5 inhibitor in the combination taught by US’593 modified by US’569, US’016, and Yoon with a hydrogen as disclosed by US’016. It would have been obvious to make this substitution, and one of ordinary skill in the art would have had a reasonable expectation of success, as US’016 teaches hydrogen as an alternative moiety in the R2 position suggesting analogous properties.
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,583,593 in view of US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018, US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012, and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739 as discussed above, and in further view of Consuegra-Fernandez, M., et al (2015) CD5 as a target for immune-based therapies Clinical Reviews in Immunology 32(2); 85-115.
US’593 modified by US’569, US’016, and Yoon teaches the method of instant claim 26 as discussed above.
The combination, however, does not disclose that the T cell surface molecule is CD5.
The teachings of Consuegra-Fernandez are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the ALK5 antibody drug conjugate taught by the combination of US’593, US’569, and Yoon to target CD5, using an anti-CD5 antibody, in place of PD-1 based on the teachings of Consuegra-Fernandez. It would have been obvious to target CD5 in place of PD-1 as Consuegra-Fernandez teaches that CD5 is a surface receptor that is found on human T lymphocytes and is positioned as an attractive target for immunotherapies. Additionally, Consuegra-Fernandez teaches that the targeting of CD5 can be used as a means of modulating immune response by targeting T cells and compares CD5 to PD-1 and CTLA-4. An ordinarily skilled artisan would have had a reasonable expectation of success as Consuegra-Fernandez teaches the targeting of CD5 for cancer treatment and also demonstrates construction of ADCs comprising CD5 had been previously produced for targeted delivery of drugs.
Claims 44-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,583,593 in view of US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018, US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012, and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739 as discussed above, and in further view of Holmgaard, R.B., et al (2018) Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as a monotherapy and in combination with checkpoint blockade Journal for ImmunoTherapy of Cancer 6(47); 1-15.
US’593 modified by US’569, US’016, and Yoon teach the method of instant claim 26 as discussed above.
The combination, however, does not disclose that the checkpoint inhibitor targets PD-1 as recited in claim 45 and is selected from those recited in claims 46-47.
The teachings of Holmgaard are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the method taught by the combination of US’593, US’569, and Yoon to use an anti-PD-1/PD-L1 antibody, such as nivolumab or durvalumab, as the checkpoint inhibitor based on the teachings of Holmgaard. An ordinarily skilled artisan would have been motivated to administer the ADC with an anti-PD-1/PD-L1 antibody, such as nivolumab or durvalumab, as Holmgaard teaches that preclinical results suggest the potential for synergy when the TGFβ and PD-1 pathway is targeted in combination. Additionally, Holmgaard teaches that the combination of Galunisertib (LY2157299 monohydrate) was currently under clinical development in combination with checkpoint inhibitors including nivolumab and durvalumab. An ordinarily skilled artisan would have had a reasonable expectation of success as the ADC taught by the combination of US’593, US’569, and Yoon includes an ALK5 inhibitor, which Yoon teaches antagonizes the TGFβ pathway. Additionally, Yoon uses LY-2157299 as a comparison to an ALK5 inhibitor, demonstrating that both function in blocking the TGFβ pathway and enhancing T cell immunity.
US 11,987,558 B1
Claims 26, 28-29, 31, 32, 37-39, 41-44, and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 11,987,558 in view of US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012, US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018 and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739.
Claims 1-2 of US’558 claim a compound having the structure
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and an HCL salt thereof.
The claims of US’558 differ from the instant claims in that the claims of US’558 do not claim that the compound is conjugated to an antibody or an antigen binding fragment that binds to a T cell surface molecule and administered in the treatment of cancer in combination with a checkpoint inhibitor.
The teachings of US’016, US’569, and Yoon are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to conjugate the compound claimed in US’558, which shares structural similarity with the compounds of US’016, which are ALK5 inhibitors, to an anti-PD-1 antibody or antibody fragment, such as that taught by US’569, and to have administered the conjugate in a method of treating cancer based on the teachings of Yoon. It would have further been obvious to coadminister a checkpoint inhibitor based on the teachings of US’569. An ordinarily skilled artisan would have been motivated to conjugate compound to a targeting moiety that targets T cells, such as the anti-PD-1 antibody, as Yoon demonstrates that ALK5 inhibitors induce ubiquitin-mediated degradation of Semad4 in CD8+ T cells in addition to the direct inhibition of R-Smad phosphorylation leading to enhanced CTL responses through depression of Eomes. Additionally, Yoon teaches that the anti-tumor effects of the inhibitors mainly depend on CD8+ T cells and that response to such antagonism mainly targets the immune system rather than the cancer cells. An ordinarily skilled artisan would have had a reasonable expectation of success as US’016 teaches conjugates comprising ALK5 inhibitors and US’569 teaches that the anti-PD-1 antibody can be used in antibody drug conjugates and that methods of making such conjugates were known in the art. It would have further been obvious to administer the conjugate in combination with a checkpoint inhibitor, such as those disclosed by US’569, as US’569 teaches the targeting of the checkpoints in combination with anti-PD-1 antibody conjugates for modulation of the tumor immunosuppressive microenvironment.
Regarding claim 28, US’558 modified by US’016, US’569, and Yoon teaches the method of instant claim 26 as discussed above.
The structure claimed in US’593 differs from the instantly claimed compound in the addition of a methyl group on the pyridine group.
As discussed above, US’016 teaches a genus in which the R2 group is hydrogen or an alkyl having 1 to 5 carbon atoms.
It would have been prima facie obvious to one of ordinary skill in the art to substitute the methyl group in the ALK5 inhibitor in the combination taught by US’558 modified by US’016, US’569, and Yoon with a hydrogen as disclosed by US’016. It would have been obvious to make this substitution, and one of ordinary skill in the art would have had a reasonable expectation of success, as US’016 teaches hydrogen as an alternative moiety in the R2 position suggesting analogous properties.
Claims 33-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 11,987,558 in view of US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012, US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018 and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739 as discussed above, and in further view of McCombs, J.R. and S.C. Owens (2015) Antibody drug conjugates: design and selection of linker, payload, and conjugation chemistry The AAPS Journal 17(2); 339-351.
The claims of US’558 modified by US’016, US’569, and Yoon teaches the method of instant claim 26 as discussed in detail above.
As discussed above, US’016 teaches that the acid-liable linker is a hydrazone-based linker.
The combination, however, does not disclose that the cleavable linker is as recited in claims 33-36.
The teachings of McCombs are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to substitute the hydrazone cleavable linker in the ALK5 conjugate taught by the combination of US’558, US’016, US’569, and Yoon with the enzymatically cleavable dipeptide linker valine-citrulline as taught by McCombs. An ordinarily skilled artisan would have been motivated to make this substitution as McCombs teaches that the Val-Cit linker was shown to be over 100 times as stable as a hydrazone linker when tested in an ADC. An ordinarily skilled artisan would have had a reasonable expectation of success as McCombs provides alternatives to the cleavable hydrazone linker for use in drug conjugates.
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 11,987,558 in view of US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012, US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018 and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739 as discussed above, and in further view of Consuegra-Fernandez, M., et al (2015) CD5 as a target for immune-based therapies Clinical Reviews in Immunology 32(2); 85-115.
US’558 modified by US’016, US’569 and Yoon teaches the method of instant claim 26 as discussed above.
The combination, however, does not disclose that the T cell surface molecule is CD5.
The teachings of Consuegra-Fernandez are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the ALK5 antibody drug conjugate taught by the combination of US’558, US’016, US’569, and Yoon to target CD5, using an anti-CD5 antibody, in place of PD-1 based on the teachings of Consuegra-Fernandez. It would have been obvious to target CD5 in place of PD-1 as Consuegra-Fernandez teaches that CD5 is a surface receptor that is found on human T lymphocytes and is positioned as an attractive target for immunotherapies. Additionally, Consuegra-Fernandez teaches that the targeting of CD5 can be used as a means of modulating immune response by targeting T cells and compares CD5 to PD-1 and CTLA-4. An ordinarily skilled artisan would have had a reasonable expectation of success as Consuegra-Fernandez teaches the targeting of CD5 for cancer treatment and also demonstrates construction of ADCs comprising CD5 had been previously produced for targeted delivery of drugs.
Claims 44-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 11,987,558 in view of US 2012/0022016 A1 (Barbeau, D.L.) 26 Jan 2012, US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018 and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739 as discussed above, and in further view of Holmgaard, R.B., et al (2018) Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as a monotherapy and in combination with checkpoint blockade Journal for ImmunoTherapy of Cancer 6(47); 1-15.
US’558 modified by US’016, US’569 and Yoon teaches the method of instant claim 26 as discussed above.
The combination, however, does not disclose that the checkpoint inhibitor targets PD-1 as recited in claim 45 and is selected from those recited in claims 46-47.
The teachings of Holmgaard are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the method taught by the combination of US’558, US’016, US’569, and Yoon to use an anti-PD-1/PD-L1 antibody, such as nivolumab or durvalumab, as the checkpoint inhibitor based on the teachings of Holmgaard. An ordinarily skilled artisan would have been motivated to administer the ADC with an anti-PD-1/PD-L1 antibody, such as nivolumab or durvalumab, as Holmgaard teaches that preclinical results suggest the potential for synergy when the TGFβ and PD-1 pathway is targeted in combination. Additionally, Holmgaard teaches that the combination of Galunisertib (LY2157299 monohydrate) was currently under clinical development in combination with checkpoint inhibitors including nivolumab and durvalumab. An ordinarily skilled artisan would have had a reasonable expectation of success as the ADC taught by the combination of US’558, US’016, US’569, and Yoon includes an ALK5 inhibitor, which Yoon teaches antagonizes the TGFβ pathway. Additionally, Yoon uses LY-2157299 as a comparison to an ALK5 inhibitor, demonstrating that both function in blocking the TGFβ pathway and enhancing T cell immunity.
17/258,889
Claims 26, 28-29, 31-36, 39-40, and 42-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24, 30-31, 34, 37-38, 47-48, 50-51, and 53-54 of copending Application No. 17/258,889 in view of Holmgaard, R.B., et al (2018) Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as a monotherapy and in combination with checkpoint blockade Journal for ImmunoTherapy of Cancer 6(47); 1-15, and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739.
App’889 claims a method of treating cancer comprising administering to a subject in need thereof an antibody-ALK5 inhibitor conjugate comprising an ALK5 inhibitor covalently linked to an antibody comprising means for binding CD5, wherein the ALK5 inhibitor has the recited structures, which are the same as the first and second structures of instant claim 26 and those of instant claims 28-29. App’889 further claims that the cancer is a solid tumor, that the conjugate is administered as part of a combination therapy regimen (claims 34 and 38).
The claims of App’889 differ from the instant claims in that App’889 does not claim that the combination therapy regimen comprises a checkpoint inhibitor.
The teachings of Holmgaard are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the claims of App’889 by further administering an anti-PD-1/PD-L1 antibody, such as nivolumab or durvalumab, based on the teachings of Holmgaard and Yoon. An ordinarily skilled artisan would have been motivated to administer the ADC with an anti-PD-1/PD-L1 antibody, such as nivolumab or durvalumab, as Holmgaard teaches that preclinical results suggest the potential for synergy when the TGFβ and PD-1 pathway is targeted in combination. Additionally, Holmgaard teaches that the combination of Galunisertib (LY2157299 monohydrate) was currently under clinical development in combination with checkpoint inhibitors including nivolumab and durvalumab. An ordinarily skilled artisan would have had a reasonable expectation of success as Yoon teaches antagonizes the TGFβ pathway with an ALK5 inhibitor and uses LY-2157299 as a comparison, demonstrating that both function in blocking the TGFβ pathway and enhancing T cell immunity.
Claims 37-38 and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-27, 30-31, 34, 37-38, 47-48, 50-51, and 53-54 of copending Application No. 17/258,889 in view of Consuegra-Fernandez, M., et al (2015) CD5 as a target for immune-based therapies Clinical Reviews in Immunology 32(2); 85-115, Holmgaard, R.B., et al (2018) Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as a monotherapy and in combination with checkpoint blockade Journal for ImmunoTherapy of Cancer 6(47); 1-15, and Yoon, J.H., et al (2013) Activin receptor-like kinase 5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby depressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 5; 1720-1739 as discussed above, and in further view of US 2018/0346569 A1 (Wang, J., et al) 6 Dec 2018.
App’889 modified by Consuegra-Fernandez, Holmgaard, and Yoon teach the method of instant claim 26 as discussed above.
The combination, however, does not disclose the conjugate targets PD-1.
The teachings of US’569 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to substitute the antibody binding CD5 in the combination of App’889, Consuegra-Fernandez, Holmgaard, and Yoon with an antibody or antibody binding fragment targeting PD-1 as taught by US’569. It would have been obvious to target PD-1 in place of CD5 as US’569 demonstrates that PD-1 was a known target on T cells in the tumor microenvironment. An ordinarily skilled artisan would have had a reasonable expectation of success as US’569 teaches the use of the disclosed anti-PD-1 antibodies in antibody drug conjugates.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments in the response filed 03/23/2026 has been fully considered in so far as they apply to the rejections of the instant office action, but are not persuasive.
With regards to the nonstatutory double patenting rejections, applicant argues that one of ordinary skill in the art, aware of the cited references, would have been motivated to develop ALK5 inhibitors as standalone small molecules, rather than as ADCs. Applicant cites Yoon and Holmgaard as demonstrating that stand alone ALK5 inhibitors were identified as suitable therapeutics. Applicant argues that one can imagine disadvantages to using the ALK5 as an ADC including costs and convenience of administration. Applicant argues that, as such, a person of ordinary skill in the art would not have been motivated to modify the cited references.
These arguments are not persuasive.
The copending application in the provisional double patenting rejection, App’889, is drawn to a method of treating cancer comprising administering an antibody drug conjugate comprising an ALK5 inhibitor conjugated to an antibody comprising means for binding CD5 and claims two of the three compounds of instant claim 26. As such, one of ordinary skill in the art would not have needed motivation to develop an ALK5 ADC as argued by applicant in the response.
With regards to the rejections over US’593 and US’558, while the art does recognize that stand alone ALK5 inhibitors are suitable for therapeutic use, the art also demonstrates that drugs conjugated to targeting moieties were known and commonly practiced in the art. For instance, US’016 teaches ALK5 inhibitors, including those with pyrazole type structures, conjugated to molecules that target Muc4. US’569 teaches antibody drug conjugates and explicitly teaches that “[m]ethods for preparing such an immunoconjugate are well known in the art.” (page 7, [0088]), a teaching which demonstrates that antibody drug conjugates were also routine in the art. As the prior art clearly suggests conjugation of drugs to targeting moieties, including antibodies, one of ordinary skill in the art would not have considered cost or convenience of administration as discouraging or criticizing the use of antibody drug conjugates. Additionally, it is noted, that applicant does not provide any support for such speculative statements other than to say that biologics, such as antibodies, are costlier than small molecule drugs to manufacture or that an orally available drug can be administered in pill form while an ADC is typically injected. Applicant does not provide any direct evidence that the art viewed cost of manufacture or administration simplicity to be a deterring factor in antibody drug conjugate development or use.
Allowable Subject Matter
Claim 30 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: Instant claim 30 is drawn to the method of claim 26 and further claims that the compound has the structure:
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In searches of the prior art, no matching structures were identified.
The following is considered to be the closest prior art:
Boys, M.L, et al (2012) Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring Bioorganic & Medicinal Chemistry Letters 22; 3392-3397. Boys discloses ALK inhibitors in table 1 on page 3393, including the following compounds:
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Compounds (7) and (9) disclosed in Boys are the closest compounds identified in the prior art. Compound (7) differs from the instantly claimed compound in the carbonyl group on R1 (where the instantly claimed compound has an amino group) as well as on the methyl group on R1. Compound (9) differs from the instantly claimed compound in the carbonyl group on R1 as well as in R2 and R3 which are in opposite positions.
Boys does not teach or suggest modification to the compounds with a reasonable expectation of success or with predictable outcomes. Additionally, in searches of the prior art, no suggestion or predictability was identified that would allow for the modification of the compounds disclosed by Boys with a reasonable expectation of success. Therefore, claim 30 was also found to be non-obvious over the prior art.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
/YVONNE L EYLER/Director, Technology Center 1600
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