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 .
Response to Amendment
In the amendment filed on 09/03/2026 Applicant cancelled claims 38-40, 42, 43 and 53, and added the new claims 61-75. Claims 41, 44-52 and 54-75 are pending; claims 44-52 and 54-60 remain withdrawn from prosecution for reasons of record. Claims 41 and 61-75 are examined.
Withdrawn claim rejections
Claim Rejections - 35 USC § 102
The rejection of claims 38 and 41 under 35 U.S.C. 102(a)(1) as being anticipated by Axten et al. (WO2018015879) is withdrawn in view of the amendments to the claims.
New claim rejections necessitated by amendment
Claim Rejections - 35 USC § 112
Claims 41 and 61-75 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). (emphasis added). See also MPEP 2163.04.
The claims are drawn to a method of preventing metastasis in a subject having a cancer comprising a primary tumor, comprising administering to the primary tumor of the subject an immunotherapy comprising:
(a) PKR-like ER kinase (PERK) inhibitor, endoplasmic reticulum (ER) stress inhibitor, and/or inositol-requiring enzyme la (IREla) inhibitor, wherein the PERK inhibitor, ER stress inhibitor, and/or IRE la inhibitor comprises a RNAi, small molecule, peptide, protein, or antibody; and
(b) an immune checkpoint inhibitor.
Further limitations add that the method comprises administering an effective amount of an additional anticancer agent or ionizing radiation to the subject.
The specification discloses treatment of mouse xenograft of Lewis lung cancer cells, B16 melanoma cells, ovarian cancer cells, pancreatic cancer cells and EG7 T lymphoblastic cells with Tauroursodeoxycholic acid (TUDCA), GSK-2606414, AMG-44,and KIRA8 (with or without anti-PD L1 antibodies). There is no indication of using additional anticancer agents or ionizing radiation.
With respect to what is in possession of, Applicant discloses that: “Our results indicate that short-term treatment with low dose PERK inhibitors promoted anti-tumor protective immunity and boosted the effectiveness of anti-PD-L1, without altering blood glucose levels or the size or insulin expression of the pancreatic islets. Despite these promising results, further pharmacological investigations evaluating the activity of PERK inhibitors is warranted as we anticipate that the dose, treatment period, route, and bioavailability could regulate their therapeutic vs. toxic effects. Alternatively, therapeutic use of cellular stress mitigating agents, such as TUDCA, could target all branches of UPR, without known toxicity. Thus, it is likely that the inhibition of PERK, or mitigation of maladaptive UPR activation, could induce dual anti-tumor and immune-stimulatory effects in tumor-bearing hosts. This remains to be tested in clinical studies and could have a major impact in the improvement of cancer immunotherapy ([0264]).
A skilled artisan would readily conclude that the Application, except for the examples disclosed, is just an aspirational project for treating all cancers and preventing their metastases.
With regard to the denomination of “cancer”, this is the name given to a collection of related diseases characterized by cellular out of control division and spreading in the surrounding or distant tissues. Cancer can start almost anywhere in the human body, which is made up of trillions of cells.
Normally, human cells grow and divide to form new cells as the body needs them. When cells grow old or become damaged, they die, and new cells take their place. When cancer develops, however, this orderly process breaks down. As cells become more and more abnormal, old or damaged cells survive when they should die, and new cells form when they are not needed. These extra cells can divide without stopping and may form growths called tumors. Many cancers form solid tumors, which are masses of tissue. Cancers of the blood, such as leukemias, generally do not form solid tumors.
There are more than 100 types of cancer. Types of cancer are usually named for the organs or tissues where the cancers form. Cancers also may be described by the type of cell that formed them, such as an epithelial cell or a squamous cell. Some categories of cancers that begin in specific types of cells are:
• Carcinomas- they are the most common type of cancer. They are formed by
epithelial cells, which are the cells that cover the inside and outside surfaces of the body. There are many types of epithelial cells, which often have a column-like
shape when viewed under a microscope. Carcinomas that begin in different
epithelial cell types have specific names:
o Adenocarcinoma is a cancer that forms in epithelial cells that produce fluids
or mucus. Tissues with this type of epithelial cell are sometimes called
glandular tissues. Most cancers of the breast, colon , and prostate are
adenocarcinomas.
o Basal cell carcinoma is a cancer that begins in the lower or basal (base)
layer of the epidermis, which is a person's outer layer of skin.
o Squamous cell carcinoma is a cancer that forms in squamous cells, which
are epithelial cells that lie just beneath the outer surface of the skin.
Squamous cells also line many other organs, including the stomach,
intestines, lungs, bladder, and kidneys. Squamous cells look flat, like fish
scales, when viewed under a microscope. Squamous cell carcinomas are
sometimes called epidermoid carcinomas.
o Transitional cell carcinoma is a cancer that forms in a type of epithelial
tissue called transitional epithelium, or urothelium. This tissue, which is
made up of many layers of epithelial cells that can get bigger and smaller,
is found in the linings of the bladder, ureters, and part of the kidneys (renal
pelvis), and a few other organs. Some cancers of the bladder, ureters, and
kidneys are transitional cell carcinomas.
• Sarcomas- they are cancers that form in bone and soft tissues, including muscle, fat, blood vessels, lymph vessels, and fibrous tissue (such as tendons and ligaments). Osteosarcoma is the most common cancer of bone. The most common types of soft tissue sarcoma are leiomyosarcoma, Kaposi sarcoma, malignant fibrous histiocytoma, liposarcoma, and dermatofibrosarcoma protuberans.
• Leukemias- they are cancers that begin in the blood-forming tissue of the bone
marrow. These cancers · do not form solid tumors. Instead, large numbers of
abnormal white blood cells (leukemia cells and leukemic blast cells) build up in the blood and bone marrow, crowding out normal blood cells. The low level of normal blood cells can make it harder for the body to get oxygen to its tissues, control bleeding, or fight infections. There are four common types of leukemia, which are grouped based on how quickly the disease gets worse (acute or chronic) and on the type of blood cell the cancer starts in (lymphoblastic or myeloid).
• Lymphomas- they are cancers that begins in lymphocytes (T cells or B cells).
These are disease-fighting white blood cells that are part of the immune system.
In lymphoma, abnormal lymphocytes build up in lymph nodes and lymph vessels,
as well as in other organs of the body. There are two main types of lymphoma:
o Hodgkin lymphoma - People with this disease have abnormal lymphocytes
that are called Reed-Sternberg cells. These cells usually form from 8 cells.
o Non-Hodgkin lymphoma - This is a large group of cancers that start in
lymphocytes. The cancers can grow quickly or slowly and can form from B
cells or T cells.
• Multiple myeloma is cancer that begins in plasma cells, another type of immune
cell. The abnormal plasma cells, called myeloma cells, build up in the bone marrow and form tumors in bones all through the body. Multiple myeloma is also called plasma cell myeloma and Kahler disease.
• Melanoma- is cancer that begins in cells that become melanocytes, which are
specialized cells that make melanin (the pigment that gives skin its color). Most
melanomas form on the skin, but melanomas can also form in other pigmented
tissues, such as the eye.
• Brain and Spinal Cord Tumors. There are different types of brain and spinal cord tumors. These tumors are named based on the type of cell in which they formed and where the tumor first formed in the central nervous system. For example, an astrocytic tumor begins in star-shaped brain cells called astrocytes, which help keep nerve cells healthy.
• Germ Cell Tumors- are a type of tumor that begins in the cells that give rise to
sperm or eggs.
• Neuroendocrine Tumors- they form from cells that release hormones into the blood in response to a signal from the nervous system. These tumors, which may make higher-than-normal amounts of hormones, can cause many different symptoms.
• Carcinoid Tumors- are a type of neuroendocrine tumor. They are slow-growing
tumors that are usually found in the gastrointestinal system (most often in the
rectum and small intestine). Carcinoid tumors may spread to the liver or other sites in the body, and they may secrete substances such as serotonin or prostaglandins, causing carcinoid syndrome.
An abbreviated list of cancer types is presented below:
A) Bone and muscle sarcomas:
■ Chondrosarcoma
■ Ewing's sarcoma
■ Malignant fibrous histiocytoma of bone/osteosarcoma
■ Osteosarcoma
■ Rhabdomyosarcoma
■ Heart cancer
B) Brain and nervous system:
■ Astrocytoma
■ Brainstem glioma
■ Pilocytic astrocytoma
■ Ependymoma
■ Primitive neuroectodermal tumor
■ Cerebellar astrocytoma
■ Cerebral astrocytoma
■ Glioma
■ Medulloblastoma
■ Neuroblastoma
■ Oligodendroglioma
■ Pineal astrocytoma
■ Pituitary adenoma
■ Visual pathway and hypothalamic glioma
C) Breast:
■ Breast cancer
■ Invasive lobular carcinoma
■ Tubular carcinoma
■ Invasive cribriform carcinoma
■ Medullary carcinoma
■ Male breast cancer
■ Phyllodes tumor
■ Inflammatory Breast Cancer
D) Endocrine system:
■ Adrenocortical carcinoma
■ Islet cell carcinoma (endocrine pancreas)
■ Multiple endocrine neoplasia syndrome
■ Parathyroid cancer
■ Pheochromocytoma
■ Thyroid cancer
■ Merkel cell carcinoma
E) Eye:
■ Uveal melanoma
■ Retinoblastoma
F) Gastrointestinal
■ Anal cancer
■ Appendix cancer
■ cholangiocarcinoma
■ Carcinoid tumor, gastrointestinal
■ Colon cancer
■ Extrahepatic bile duct cancer
■ Gallbladder cancer
■ Gastric (stomach) cancer
■ Gastrointestinal carcinoid tumor
■ Gastrointestinal stromal tumor (GIST)
■ Hepatocellular cancer
■ Pancreatic cancer, islet cell
■ Rectal cancer
G) Genitourinary and gynecologic
■ Bladder cancer
■ Cervical cancer
■ Endometrial cancer
■ Extragonadal germ cell tumor
■ Ovarian cancer
■ Ovarian epithelial cancer (surface epithelial-stromal tumor)
■ Ovarian germ cell tumor
■ Penile cancer
■ Renal cell carcinoma
■ Renal pelvis and ureter, transitional cell cancer
■ Prostate cancer
■ Testicular cancer
■ Gestational trophoblastic tumor
■ Ureter and renal pelvis, transitional cell cancer
■ Urethral cancer
■ Uterine sarcoma
■ Vaginal cancer
■ Vulvar cancer
■ Wilms tumor
F) Head and neck
■ Esophageal cancer
■ Head and neck cancer
■ Nasopharyngeal carcinoma
■ Oral cancer
■ Oropharyngeal cancer
■ Paranasal sinus and nasal cavity cancer
■ Pharyngeal cancer
■ Salivary gland cancer
■ Hypopharyngeal cancer
G) Hematopoietic
■ Acute biphenotypic leukemia
■ Acute eosinophilic leukemia
■ Acute lymphoblastic leukemia
■ Acute myeloid leukemia
■ Acute myeloid dendritic cell leukemia
■ AIDS-related lymphoma
■ Anaplastic large cell lymphoma
■ Angioimmunoblastic T-cell lymphoma
■ B-cell prolymphocytic leukemia
■ Burkitt's lymphoma
■ Chronic lymphocytic leukemia
■ Chronic myelogenous leukemia
■ Cutaneous T-cell lymphoma
■ Diffuse large B-cell lymphoma
■ Follicular lymphoma
■ Hairy cell leukemia
■ Hepatosplenic T-cell lymphoma
■ Hodgkin's lymphoma
■ Hairy cell leukemia
■ lntravascular large 8-cell lymphoma
■ Large granular lymphocytic leukemia
■ Lymphoplasmacytic lymphoma
■ Lymphomatoid granulomatosis
■ Mantle cell lymphoma
■ Marginal zone 8-cell lymphoma
■ Mast cell leukemia
■ Mediastinal large 8 cell lymphoma
■ Multiple myeloma/plasma cell neoplasm
■ Myelodysplastic syndromes
■ Mucosa-associated lymphoid tissue lymphoma
■ Mycosis fungoides
■ Nodal marginal zone B cell lymphoma
■ Non-Hodgkin lymphoma
■ Precursor 8 lymphoblastic leukemia
■ Primary central nervous system lymphoma
■ Primary cutaneous follicular lymphoma
■ Primary cutaneous immunocytoma
■ Primary effusion lymphoma
■ Plasmablastic lymphoma
■ Sezary syndrome
■ Splenic marginal zone lymphoma
■ T-cell prolymphocytic leukemia
H) Skin
■ Basal cell carcinoma
■ Squamous cell carcinoma
■ Skin adnexal tumors (e.g. sebaceous carcinoma)
■ Melanoma
■ Merkel cell carcinoma
■ Sarcomas of primary cutaneous origin (e.g. dermatofibrosarcoma protuberans)
■ Lymphomas of primary cutaneous origin (e.g. mycosis fungoides)
I) Thoracic and respiratory
■ Bronchial adenomas/carcinoids
■ Small cell lung cancer
■ Mesothelioma
■ Non-small cell lung cancer
■ Pleuropulmonary blastoma
■ Laryngeal cancer
■ Thymoma and thymic carcinoma
J) HIV/ AIDS related
■ AIDS-related cancers
■ Kaposi sarcoma
K) Unsorted
■ Epithelioid hemangioendothelioma (EHE)
■ Desmoplastic small round cell tumor
■ Liposarcoma
(https://en .wikipedia .org/wiki/List_of_cancer_types- accessed 05/22/2020;
https://www.cancer.gov/about-cancer/understanding/what-is-cancer) .
This represents a short list of the diseases that are to be treated by the method of treatment claimed by the instant Application and is illustrative of the breadth of claims. Any method of treatment comprises the composition to be administered, a range dosage per kg or m2, a treatment regimen and metrics for determining if the goal of the treatment has been achieved. The specification does not address these parameters since it does not treat any subject but mouse xenografts of Lewis lung cancer cells, B16 melanoma cells, ovarian cancer cells, pancreatic cancer cells and EG7 T lymphoblastic cells.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
A “representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Given the extremely vast number of cancer cell types, a skilled artisan would considered that Applicant was not in possession of a representative number of species so as to claim possession of the genus of the independent claims 41 and 68.
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.
Claims 41 and 61-75 are rejected under 35 U.S.C. 103 as being unpatentable over Fournie et al.(WO 2020070053) in view of Calvo et al. (A PERK inhibitor that blocks HER2 driven tumorigenesis and suppresses metastasis by targeting single disseminated tumor cells. Cancer Research, Vol. 76, No. 7, Supp. Supplement. Abstract Number: A38. Meeting Info: AACR Special Conference on Tumor Metastasis. Austin, TX, United States. 30 Nov 2015-03 Dec 2015).
The claims are drawn to a method of preventing metastasis in a subject having a cancer comprising a primary tumor, comprising administering to the primary tumor of the subject an immunotherapy comprising:
(a) PKR-like ER kinase (PERK) inhibitor, endoplasmic reticulum (ER) stress inhibitor, and/or inositol-requiring enzyme la (IREla) inhibitor, wherein the PERK inhibitor, ER stress inhibitor, and/or IRE la inhibitor comprises a RNAi, small molecule, peptide, protein, or antibody; and
(b) an immune checkpoint inhibitor.
The immunotherapy induces abscopal anti-tumor effects that protect against regrowth of secondary tumors.
Further limitations are drawn to the exact inhibitors used PERK inhibitor, ER stress inhibitor, and/or IREla inhibitor comprises GSK-2606414, AMG-44, Tauroursodeoxycholic acid (TUDCA), MKC8866, or KIRA8. The checkpoint inhibitors are PD-1 inhibitor, a PD-L1 inhibitor and CTLA-4 inhibitor (and selected from nivolumab, pembrolizumab, atezolizumab, avelumab, ipilimumab)
Fournie et al. teaches a method for targeting the regulation of immune response in a subject with cancer comprising administering to the subject a therapeutically effective amount of at least one inhibitor of stress granule formation. The reference also disclosed a method of therapy, comprising administering to a subject a therapeutically effective amount at least one inhibitor of stress granule formation that reduces the expression of an immune checkpoint protein, wherein said administration enhances the proliferation, migration, persistence and/or activity of cytotoxic T lymphocytes (CTLs) in the subject. The inhibitor of stress granule formation is selected from the group
consisting of GCN2, PERK, PKR, HRI, mTOR, CK2, DYRK3, AMPK, ROCK1, S6K1,
10 S6K2 and OGT (claims 1-5, 9-10). The inhibitor is administered with an immune checkpoint inhibitor includes PD-1 antagonists, PD-L1 antagonist, PD-L2 antagonists, CTLA-4 antagonists, VISTA antagonists, TIM-3 antagonists, LAG-3 antagonists, IDO antagonists, KIR2D antagonists, A2AR antagonists, B7-H3 antagonists, B7-H4 antagonists, and BTLA antagonists (claim 12).
The reference does not specifically teach a method of preventing metastasis in a subject having a cancer comprising a primary tumor, comprising administering to the primary tumor of the subject an immunotherapy. However, the reference indicated that: “As used herein, the term "cancer" has its general meaning in the art and includes, but is not limited to, solid tumors and blood-borne tumors. The term cancer includes diseases of the skin, tissues, organs, bone, cartilage, blood and vessels. The term "cancer" further encompasses both primary and metastatic cancers.”
Calvo et al. teaches that the unfolded protein response (UPR) is a critical survival and adaptation pathway in cancer cells. The endoplasmic reticulum kinase PERK serves as a survival UPR factor for different tumor types, including those driven by the oncogene HER2, and it can also promote survival of dormant cancer cells. The reference evaluated the effect of a potent and selective new PERK inhibitor (LY4) on MMTVHER2driven tumorigenesis that, through genetic experiments, was shown to depend on a full complement of PERK for progression. Early MMTVHER2+ lesions require PERK for HER2driven alterations in ductal epithelial organization, and that LY4 impairs the expansion of established HER2+ tumor cells in 3D organotypic cultures and in vivo. Importantly, PERK inhibition blunted metastasis development. This effect was linked to the ability of the PERK inhibitor to eradicate solitary HER2+ disseminated tumor cells that, in their majority, are dormant or slow cycling, but that represent the seeds for further metastases.
With respect to the specific checkpoint inhibitors and specific PERK inhibitors, the art was using these compounds for a relative long time and, as such, they were known in the art. Exemplary references are: Gill et al. (A reality check of the accelerated approval of immune-checkpoint inhibitors. Nature 16, 657-658, 2019) and Chintha et al. (Molecular modeling provides a structural basis for PERK inhibitor selectivity towards RIPK1. Royal Soc. Of Chemistry, 10, 397-375, 2020), respectively.
It would have been obvious for a person of ordinary skill in the art at the time that the invention was filed to have used the teachings of Fournie et al and treat primary tumors to prevent metastases, according to Calvo et al. with a reasonable expectation of success. This is because the compounds were known in the art and a skilled artisan would have used known and tested techniques and compounds for solving a known problem.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLY GERALD STOICA whose telephone number is (571)272-9941. The examiner can normally be reached M-F 8-5 EST.
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, Joanne Hama can be reached at 571-272-2911. 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.
ELLY-GERALD STOICA
Primary Examiner
Art Unit 1647
/Elly-Gerald Stoica/Primary Examiner, Art Unit 1647
Prosecution Insights