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 1-9, 14-19, 22, 24-26, and 45 are currently pending and under prosecution.
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 24-26 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 treatment of NELL2 positive Ewing’s sarcoma, does not reasonably provide enablement for treatment of all NELL2 positive cancers, including neuroblastoma and brain 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.
BREADTH OF THE CLAIMS: Claim 24 recites a method of treating a NELL2 positive cancer in a subject in need, the method comprising administering to the subject having cancer a therapeutically effective amount of the isolated antibody of claim 1. Claim 25 recites wherein the cancer is Ewing sarcoma, neuroblastoma or a brain cancer. Claim 26 recites wherein the brain cancer is glioblastoma or medulloblastoma.
PRESENCE OR ABSENCE OF EXAMPLES: The instant specification discloses the following: Example 1 demonstrates that NELL2 as a target of Ewing sarcoma cell growth. Example 2 demonstrates methods of targeting NELL2 via monoclonal antibodies for Ewing sarcoma in vivo. The instant specification recites “In addition to Ewing sarcoma, it was found that neuroblastoma, medulloblastoma, and glioblastoma also depend on NELL2 signaling, suggesting that these cancers can also be treated by administration of anti-NELL2 monoclonal antibodies.” [Example 2] The instant specification does not provide any other examples of the instantly claimed antibody for the treatment of NELL2 positive cancers outside the scope of Ewing sarcoma cells.
STATE OF THE ART: A search of relevant art discloses that NELL2 pathophysiology has dual functionality in various context. Li et al (Deciphering the functions of NELL2 in tumorigenesis and beyond. Front. Immunol. 17:1780909; 2026) teaches that NELL2 may behave as a tumor oncogene in certain cancers, such as NSCLC and Ewing’s sarcoma, yet functions as a tumor suppressor in hepatocellular carcinoma (HCC), gastric, renal and osteosarcoma. [see pg 2, 1st column] Li et al teaches that the role of NELL2 in tumorigenesis is complex and context-dependent, particularly with regard to its actions and signaling regulation. [pg 7-8 “The roles of NELL2 in tumors”] Furthermore, Cavaco et al (Antibodies for the Treatment of Brain Metastases, a Dream or a Reality? Pharmaceutics. 2020 Jan 13;12(1):62) teach the barriers and challenges of administering antibodies for the treatment of brain cancer, and antibodies crossing the blood brain barrier. Cavaco et al teaches that the blood brain barrier remains to be the most significant obstacle to the efficient delivery of small-molecule drug and therapeutic proteins. [pg 4, 1st paragraph] Cavaco teaches that poor blood brain penetration of antibodies renders them ineffective, and that it is imperative to find strategies that allow for antibody translocation across the blood brain barrier. [pg 9, last paragraph] Thus, the prior art demonstrates the challenges of targeting all NELL2 positive cancers, as well as the challenges of targeting brain cancers with large molecules, such as antibodies.
PREDICITABILITY: The specification lacks the critical steps necessary in presenting some type of response in a population of hosts deemed necessary to treat all types of NELL2 positive cancers. There is no evidence in the instant application or the art that as noted in the prior that demonstrate that the claimed antibody can treat all NELL2+ positive cancers, such as brain cancers and neuroblastoma, as claimed. The amount of experimentation to require to formulate such guidance would be enormous; one would have to demonstrate the efficacy of the claimed antibody in several models across several different types of NELL2 positive cancers, as well as demonstrating that the claimed antibody would cross the blood brain barrier. Thus, considering the high level of skill in the art, the state of the art, the level of predictability, and the guidance and examples provided, the experimentation required to enable the full scope of the claimed invention would not be reasonable.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine claimed antibody is administered to which population of subjects could predictably treat all NELL2 positive cancers 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 antibody treats as claimed. 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.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5 and 6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 5 and 6 recite that the isolated antibody of claim 4, wherein a light chain variable region has an amino acid sequence that is at least 90% identical to amino acid sequence of SEQ ID NO: 4 and wherein a heavy chain variable region has an amino acid sequence that is at least 90% identical to amino acid sequence of SEQ ID NO: 14, respectively. It is unclear whether claims 5 and 6 are reciting additional variable sequences, or if they are referring to the light chain and heavy chain variable regions of claim 4.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 9 and 14 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 9 recites that the isolated antibody of claim 1 binds to human NELL2. Claim 14 recites that the isolated antibody of claim 1 inhibits binding of human NELL2 to human Robo3. Claim 1 recites that the isolated antibody comprises a light chain variable region comprising CDRL-1-3 amino acid sequences 1-2-3, and a heavy chain variable region comprising CDRH-13 11-12-13. The instant specification discloses on page 44 “Anti-NELL2 antibodies” that the disclosed antibodies bind to NELL2 and block or inhibit the NELL2/Robo3 interaction [pg 4, lines 1-6]. Example of this antibody includes the instantly claimed sequences of the isolated antibody of claim 1. [pg 4 lines 23-32] Thus, it is not clear how dependent claims 9 and 14 further limit independent claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claims 5 and 6 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 5 and 6 recite that the isolated antibody of claim 4, wherein a light chain variable region has an amino acid sequence that is at least 90% identical to amino acid sequence of SEQ ID NO: 4 and wherein a heavy chain variable region has an amino acid sequence that is at least 90% identical to amino acid sequence of SEQ ID NO: 14, respectively. Claim 4 recites an isolated antibody comprising a light chain variable region amino acid sequence of SEQ ID NO: 4 and a heavy chain variable region amino acid sequence of SEQ ID NO: 14. Given claims 5 and 6 broaden the scope of claim 4, which is limited to specific sequences of the light chain and heavy chain variable regions, the limitations of claims 5 and 6 are outside the scope of claim 4 and do not further limit the limitations of claim 4. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Allowable Claims
Claims 1-4, 7-8, 15-19, 22, and 45 are allowed. The sequences of the instantly claimed antibody are novel. There is no art that teaches a NELL-2 antibody comprising the instantly claimed sequences.
Conclusion
Status of claims: Claims 5, 6, 9, 14, and 24-26 are rejected. Claims 1-4, 7-8, 15-19, 22, and 45 are allowed.
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.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
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