Patent Application 17768906 - COMPOSITION COMPRISING EMP3 INHIBITOR FOR - Rejection

Patent Application 17768906 - COMPOSITION COMPRISING EMP3 INHIBITOR FOR

Title: COMPOSITION COMPRISING EMP3 INHIBITOR FOR INHIBITING GROWTH OF CANCER STEMCELL AND USE THEREOF

Application Information

• Invention Title: COMPOSITION COMPRISING EMP3 INHIBITOR FOR INHIBITING GROWTH OF CANCER STEMCELL AND USE THEREOF
• Application Number: 17768906
• Submission Date: 2025-04-09T00:00:00.000Z
• Effective Filing Date: 2022-04-14T00:00:00.000Z
• Filing Date: 2022-04-14T00:00:00.000Z
• National Class: 424
• National Sub-Class: 139100
• Examiner Employee Number: 96419
• Art Unit: 1646
• Tech Center: 1600

Rejection Summary

• 102 Rejections: 0
• 103 Rejections: 2

Cited Patents

No patents were cited in this rejection.

Office Action Text

    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 .
DETAILED ACTION
Claims 1-18 and 21 are pending and currently under prosecution.
Claim Objections
Claims 1, 10, 16, and 21 are objected to because of the following informalities: the claims recite a method of administering epithelial membrane protein 3 (EMP3) inhibitor. The claims should recite a method of administering an epithelial membrane protein 3 (EMP3) inhibitor. Appropriate correction is required.

Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.

The following is a quotation of the first paragraph of pre-AIA  35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

Claims 1-18 and 21 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. This is a WRITTEN DESCRIPTION rejection. 
The claims recite a step of administering an epithelial membrane protein 3 (EMP3) inhibitor for the following methods: 
A method for inhibiting growth of cancer stem cells;
A method for treating cancer;
A method for assisting a radiation anticancer treatment;
A method for enhancing the sensitivity of cancer cells to radiation.
The claims recite that the EMP3 inhibitor:
 is an oligonucleotide, which inhibits the expression of EMP3 genes
antibody that inhibits the activity of EMP3 protein or a ligand protein for EMP3, or an antigen binding fragment thereof; wherein the antibody binds to amino acid sequence set forth in SEQ ID NO: 4
has the ability to inhibit the self-renewal potential, invasiveness, and migration ability of cancer stem cells. 
 enhances sensitivity of cancer cells, including cancer stem cells, to radiation. 
Thus, the claims identify the EMP3 inhibitor by function only, wherein the function is recited above in (a)-(h). No structure of the EMP3 inhibitor is recited. 
The instant specification discloses the following regarding the EMP3 inhibitor: 
Table 1 demonstrates the siRNA sequence for the EMP3 gene. [0043-0045]
Figure 2 and Example 2 demonstrate use of an EMP3 antibody; however, no structure is recited. 
Thus, the instant specification describes a single EMP3 inhibitor that functions as claimed. The specification fails to disclose any other inhibitors, or structural sequences required of the EMP3 antibody, to possess the function of (a)-(h) as recited above. 
To provide adequate written description and evidence of possession of the claimed inhibitor genus, the instant specification can structurally describe representative inhibitors, oligonucleotides, and/or antibodies that function as recited above in (a)-(h), or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).  A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.  
Although Applicants may argue that it is possible to screen for inhibitors that bind  EMP3 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘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.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future inhibitors yet to be discovered that may function as claimed. The EMP3 antigen provides no information about the structure of any inhibitor that binds to it.
In this case, the only factor present in the claims is a recitation of the inhibitors function, which is recited above in (a)-(h). The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only a single exemplary inhibitor that functions as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the inhibitor does, rather than what it is. The specification fails to provide any structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of sequences or structures for the genus of inhibitors that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
Given the lack of representative examples to support the full scope of the claimed inhibitors used in the claimed method, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs that provide EMP3-binding function and functions as recited above, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies that bind EMP3 and function as recited above in (a)-(h) that is required to practice the claimed invention.  Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Claims 10-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating cancer, does not reasonably provide enablement for preventing cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. 
The claims recite a method for preventing or treating cancer, the method comprising a step of administering EMP3 inhibitor to a subject in need thereof, wherein the cancer has ALDH1-overexpressing cancer stem cell properties. 
Regarding prevention of cancer:

(1) State of the art 
A search of relevant art, does not reveal any demonstration that an EMP3 inhibitor prevents cancer.  Szabo et al (Selecting targets for cancer prevention: where do we go from here?. Nat Rev Cancer 6, 867–874; 2006) teaches the intricacies and complications of cancer prevention. Szabo teaches that rapidly expanding understanding of the biology of carcinogenesis in many different organs provides many potential targets for intervention, however, the translation of these concepts into healthcare strategies requires an intensive efficacy and safety assessment process that spans from preclinical to phase I–III clinical testing. Szabo teaches that in addition to efficacy and toxicity concerns of cancer drugs targeting functions, there are a number of practical issues that should be considered, including drug formulation and dosing schedule to ensure adherence, as well as the cost. Szabo also teaches that in some cases the targets selected for drug therapy may even cause harm. [Whole document[ 
(2) Presence or Absence of examples
The specification does not provide any examples of an EMP3 inhibitor and preventing cancer. The examples in the specification disclose the use of an EMP3 inhibitor for treatment of cancer. There are no examples in the specification that disclose the prevention of cancer comprising administering an EMP3 inhibitor. The specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent cancer with an EMP3 inhibitor. 
Predictability 
The specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent cancer. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that administration of an EMP3 inhibitor prevents the onset of cancer in subjects as claimed.
Quantity of Experimentation 
Undue experimentation would be required to determine what EMP3 inhibitor is administered to which population of subjects could predictably prevent cancer as claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining whether the claimed EMP3 inhibitor prevents cancer. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.

Claim(s) 1-3, 5, 9-11, and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Hsieh et al. (Targeting EMP3 suppresses proliferation and invasion of hepatocellular carcinoma cells through inactivation of PI3K/Akt pathway. Oncotarget. 2015; 6(33): 34859-34874), in view of Ernst et al (Genomic and Expression Profiling of Glioblastoma Stem Cell–Like Spheroid Cultures Identifies Novel Tumor-Relevant Genes Associated with Survival. Clin Cancer Res 1 November 2009; 15 (21): 6541–6550) and Tomita et al (Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget. 2016;7(10):11018-11032)
Regarding claims 1, 9, 10, and 15, Hsieh teaches a method of inhibiting growth of cancer cells and treating cancer, the method comprising a step of administering an epithelial membrane protein 3 (EMP3) inhibitor to a subject in need; wherein the cancer is liver cancer. [Whole document] 
Regarding claims 2, 3, 12 and 13, Hsieh teaches that the inhibitor is an oligonucleotide, and inhibits the expression of the EMP3 gene. Hsieh teaches that the oligonucleotide is a shRNA. [pg 34861] 
Hsieh teaches that epithelial membrane protein-3 (EMP3) is expressed on most tissues, and teaches that EMP3 is a tumor suppressor gene in glioma, neuroblastoma, and non-small cell lung cancer has been demonstrated to promote cell proliferation, migration, and invasiveness. Hsieh teaches and demonstrates that EMP3 is highly expressed in tumorous tissues compared to non-tumorous tissues, and that overexpression is clinically associated with poor patient survival and metastasis-free survival. Regarding claim 5, Hsieh teaches that knockdown of EMP3 reduced cell proliferation, arrested cell cycle at G2 phase, and inhibited the abilities of cell migration and expression. [pg 34860]  
	However, Hsieh does not teach: (1) that the cancer cells are cancer stem cells, and (2) that the cancer stem cells are cancer cells in which ALDH1 protein is overexpressed. 
	Ernst teaches and demonstrates DNA copy number abnormalities in tumor stem-cell cultures, where they are derived from glioblastoma. Ernst teaches that protein expression level of EMP3 was associated with overall survival and clinical outcome of glioma patients. Ernst demonstrates that overall survival decreased in patients with high EMP3 levels. Ernst teaches that high EMP3 expression was significantly associated with shorter OS in astrocytic glioma patients in univariate analysis, a finding related to the association of EMP3 overexpression with primary glioblastoma.  Ernst teaches glioma stem cell–like cells display increased tumorigenicity and resistance to radiation treatment both in cell culture and in the brains of immunocompromised mice. [Figure 3B, Table 1, 6542-6546]
Tomita teaches that cancer cell-acquired drug resistance is associated with the transcriptional activation of ALDH1 expression. Tomita teaches that ALDH1 is a marker of a normal tissue stem cells and cancer stem cells, and that high activity of ALDH1 is associated with poor cancer prognosis. [Whole document] 
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer stem cells, including cancer cells that overexpress the ADLH1 protein and where the proportion of cancer stem cells in a cell group is 10% or greater, in the method of Hseih. One would have been motivated to, and have a reasonable expectation of success, because: (1) Hsieh teaches a method of treating cancer cells, comprising administering an EMP3 inhibitor, (2) Hsieh teaches that EMP3 is a tumor suppressor gene in cancers, such as glioma and neuroblastoma, and that overexpression leads to poor clinical outcomes, (3) Ernst teaches that high expression was associated with shorter overall survival, and demonstrates this in cancer stem cells, and (4)  Tomita teaches that ALDH1 is a marker in cancer stem cells, and high activity is associated with poor cancer prognosis. 
Hsieh recognizes the need in the art to treat cancer, including cancer stem cells, comprising administering an EMP3 inhibitor. Given the recognized need to treat cancer and cancer stem cells that overexpress ALDH1, given the known effect of EMP3 and ALDH1 on cancer prognosis, and given the known success for treating cancer comprising administering an EMP3 inhibitor, one of skill in the art could have pursued treating cancer stem cells, including those that express ALDH1, with the EMP3 inhibitor of Hsieh, with a reasonable expectation of success.

Claim(s) 16-18 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Hsieh et al. (Targeting EMP3 suppresses proliferation and invasion of hepatocellular carcinoma cells through inactivation of PI3K/Akt pathway. Oncotarget. 2015; 6(33): 34859-34874), Ernst et al (Genomic and Expression Profiling of Glioblastoma Stem Cell–Like Spheroid Cultures Identifies Novel Tumor-Relevant Genes Associated with Survival. Clin Cancer Res 1 November 2009; 15 (21): 6541–6550) and Tomita et al (Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget. 2016;7(10):11018-11032), as applied to claims 1-3, 5, 9-10, and 12-14 above [combined references] and further in view of Chen et al (Improving radiotherapy in cancer treatment: Promises and challenges. Oncotarget. 2017;8(37):62742-62758. Published 2017 Jun 8)
The teachings of the combined references are recited above. However, they do not explicitly teach a method for assisting a radiation anticancer treatment. 
	Chen teaches that radiotherapy is used at least two-thirds of cancer treatments and that combination of radiotherapy with other cancer target treatments allows for improved treatment efficacy of radiotherapy and personalized medicine. [Whole document] 
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use an EMP3 inhibitor to assist radiation anticancer treatment. One would have been motivated to, and have a reasonable expectation of success, because: (1) Hsieh teaches a method of treating cancer cells, comprising administering an EMP3 inhibitor, (2) Ernst teaches that high expression was associated with shorter overall survival, and demonstrates this in cancer stem cells, (3) Ernst teaches glioma stem cell–like cells display increased tumorigenicity and resistance to radiation treatment both in cell culture and in the brains of immunocompromised mice, and (4) Chen teaches the use of cancer therapeutics in combination with radiation therapy for personalized medicine. Given the recognized need to treat cancer, and given the known need to treat cancer that is radiation sensitive, and given the known success for treating cancer comprising administering an EMP3 inhibitor, one of skill in the art could have pursued assisting radiation anti-cancer treatment comprising administering an EMP3 inhibitor, with a reasonable expectation of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 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, Janet Epps-Smith can be reached on (571) 272-0757. 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.





/SARAH A ALSOMAIRY/Examiner, Art Unit 1646                                                                                                                                                                                                        
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600