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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, the certified copy of CN 202110037655.6 is not a certified English translation. Therefore, the claims were examined with the effective filing date of January 12, 2022, which is the filing date of PCT/CN 2022/071621.
Claim Objections
Claim 12 is objected to because of the following informalities: claim 12 lines 4-6 contains a typo where a duplicate of claim 13 follows the period. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 3 is 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.
Claim 3 recites the limitation "the amino acid sequence" in line 1. There is insufficient antecedent basis for this limitation in the claim. Examiner suggests deleting the limitation “the amino acid sequence of” from line.
Additionally, claim 3 recites that the antibody has at least 90% identity to an amino acid sequence selected from the group which includes SEQ ID NO: 70. SEQ ID NO: 70 is a 118 amino acid sequence which is 100% identical to SEQ ID NO: 69. The latter sequence is identified in Table 2 on pages 31-32 as a VH sequence. SEQ ID NO: 70 is Table 2 is identified as a scFv, which should comprise both a VH and VL. Again, SEQ ID NO: 70 is 100% identical to SEQ ID NO: 69 – SEQ ID NO: 70 only comprises a VH.
Claim Rejections - 35 USC § 112(d)
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 3 and 8 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 3 recites that the antibody of claim 1, which recites antibodies comprising 3 VH CDRs and 3 VL CDRs, has at least 90% identity to an amino acid sequence selected from the group which includes SEQ ID NO: 70. SEQ ID NO: 70 is a 118 amino acid sequence which is 100% identical to SEQ ID NO: 69. The latter sequence is identified in Table 2 on pages 31-32 as a VH sequence. SEQ ID NO: 70 is Table 2 is identified as a scFv, which should comprise both a VH and VL. Again, SEQ ID NO: 70 is 100% identical to SEQ ID NO: 69 – SEQ ID NO: 70 only comprises a VH. Thus, the inclusion of SEQ ID NO: 70 broadens the scope of claim 1, from which claim 3 depends, to include an antibody which comprises only the VH of SEQ ID NO: 70 and the 3 CDRs found within.
Claim 8 recites a multispecific antibody comprising the anti-ROR1 antibody of claim 1 and “one or more second antibodies”. The limitations “second antibodies” in combination with “one or more” is unclear. For instance, if the multispecific antibody comprises: 1. the anti-ROR1 antibody and 2. one second (non-anti-ROR1) antibody, the resulting structure is a bispecific antibody. This scenario is understood and clear. When the multispecific antibody comprises: 1. the anti-ROR1 antibody, 2. one second (non-anti-ROR1) antibody, and 3. one second (non-anti-ROR1) antibody, do the two second antibodies have to be the same? When there are more than one second antibody, do each of the second antibodies bind the same epitope? Do each of the second antibodies bind to the same molecule? Paragraph 0086 of the instant Specification provides support for multispecific antibodies binding two, three, or more different biomolecules. Using the word “additional” in place of “second” may be more appropriate.
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.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 25 is 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 a method for treating diseases associated with ROR1 expression comprising administering the engineered immune cell of claim 17, does not reasonably provide enablement for a method for preventing and/or diagnosing diseases associated with ROR1 expression comprising administering the engineered immune cell of claim 17. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 25 is broad, encompassing the diagnosis, prevention, and/or treatment of any disease associated with ROR1 expression by administering the engineered immune cell of claim 17. The engineered immune cell is any immune cell comprising a recombinant receptor which comprises the anti-ROR1 antibody of claim 1. Regarding diseases associated with ROR1 expression, Borcherding et al. (Protein Cell. 5 (7): 496-502; Published: April 22, 2014) teaches that ROR1 is expressed on fetal and cancerous tissues.
While the level of ordinary skill in the art is high, the level of unpredictability in the art is also high. Cancer development is understood to begin with genetic alteration resulting in karyotypic instability and malignant growth; see Pitot et al. (Cancer. 73(3): 962-970; Published: August 1, 1993). The initiation, promotion, and progression of this genetic instability is multifactorial and can be brought about by a plethora of chemical, physical, or biologic carcinogens; see Pitot et al. Following the development of a single malignant cell, several enabling characteristics or hallmarks, including sustained proliferative signaling, avoidance of apoptosis, and immune evasion, further the progression of cancer; see Hanahan et al. (Cell. 144(5): 646-674; Published: March 4, 2011). And, while there exist several models for introducing genetic instability, there is currently no animal model to recapitulate the transition from immune surveillance to immune evasion and escape.
The nature of carcinogenesis clearly lies in genetic instability and, thus, a mode of cancer prevention should aim to reverse genetic instability. Yet, the nature of this invention aims to redirect engineered immune cells to malignant ROR1-expressing cells. Thus, the invention addresses immune evasion, an enabling characteristics or hallmarks of cancer, but not the initiation itself.
Applicant has demonstrated the efficacy of targeting ROR1-expressing MDA-MB-231 cells or Hs-578T cells with an anti-ROR1 CAR T cell. However, Applicant has not demonstrated that the claimed engineered immune cells are capable of preventing cancer. Nor has Applicant provided any guidance regarding preventative treatment, including preventative dosing regimens, how to identify a subject how would benefit from preventative treatment, or when to initiate preventative treatment.
Additionally, regarding diagnosing ROR1 associated disease, the claims are drawn to a method of administering an immune cell comprising a recombinant receptor which comprises the anti-ROR1 antibody. A method for diagnosing comprising administering an antibody conjugate of claim 21 wherein the functional structure is a detectable marker would be enabled. There is no guidance in the instant Specification regarding how to diagnose disease by administering an anti-ROR1 engineered immune cell. Further, the infusion of engineered immune cells expressing a recombinant receptor is associated with severe adverse effects; see Sterner et al. (Blood Cancer Journal. 11: 69; Published: April 6, 2021). There is no guidance in the disclosure regarding under what conditions such a method, with the associated potential for life-threatening adverse effects, would be appropriate for merely diagnosing disease.
The amount of experimentation required to formulate such guidance would be enormous. One would have to demonstrate the efficacy of the engineered immune cells in several models inducing genetic instability across several different types of cancers and determine the appropriate regimen (doses and frequency) for use of the combination or composition in a preventative setting. Further, one would have to conduct population analysis to identify definitive characteristics which indicate that a subject is at risk of developing any cancer to a degree that would outweigh potential adverse effects of treatment with the claimed combination or composition.
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.
Allowable Subject Matter
Claims 1, 2, 6, 7, 10, 11, 13, 14, 17-21, 23, and 24 are allowed.
The following is a statement of reasons for the indication of allowable subject matter:
All claims require an anti-ROR1 antibody recited in claim 1. The anti-ROR1 antibodies comprising the CDR combinations of claim 1 are novel and nonobvious.
The closest prior art is Chen et al. (WO 2016/115559 A1: Published: July 21, 2016) which teaches anti-ROR1 antibodies, anti-ROR1 antibody-drug conjugates, and chimeric antigen receptors comprising anti-ROR1 antibodies.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 7:30am - 5:00pm.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682