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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 12, 2025 has been entered.
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
3. Applicant’s amendment filed August 12, 2025 is acknowledged. Claims 3-4,11-19 and 21-31 are cancelled. Claims 1-2 and 5-10 are amended. Claims 32-40 are newly added. Claims 1-2, 5-10, 20 and new claims 32-42 are pending in this application. Claims 21-22, 24-25 and 30 are withdrawn with traverse (filed on 07/22/2024) from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on July 22, 2024.
4. Claims 1-2, 5-10, 20 and 32-40 are under examination with respect to HTT and Huntington’s disease in this office action.
5. Applicant’s arguments filed on August 12, 2025 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Withdrawn
6. Th objection to claims 1, 6, 9 and 27-31 is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 27-31.
The rejection of claims 23, 26-29 and 31 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot because the claims are canceled.
The rejection of claims 23, 26-29 and 31 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, lack of scope of enablement is moot because the claims are canceled.
The rejection of claims 23, 26-29 and 31 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 is moot because the claims are canceled.
Claim Rejections/Objections Maintained
In view of the amendment filed on August 12, 2025, the following rejections are maintained.
Claim Rejections - 35 USC § 112
7. 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 1-2, 5-10, 20 and 32-40 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 pre-AIA the applicant regards as the invention. The rejection is maintained for the reasons of record and the reasons set forth below.
Response to Arguments
On p. 12-13 of the response, Applicant argues that the rejection has been overcome in view of amendment to the claims and cancelation of claims 23, 26-29 and 31.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant' s arguments, the examiner asserts that based on MPEP§2171-MPEP§2173, claims 1-2, 5-10, 20 and 32-40 are indefinite because:
i. The term “reducing level of a protein with abnormally expanded polyglutamine (polyQ)” in independent claim 1, the term "enhances the binding”, the term “reduce the level of the protein” in independent claims 1 and 32, the term “ameliorate the Huntington’s disease related behavior defects” in independent claim 32 or “attenuates the apoptosis” in claim 41 is a relative term which renders the claim indefinite. The term “reducing level of a protein….”, "enhances the binding", “reduce the level of the protein”, “ameliorate the Huntington’s disease….” or “attenuates the apoptosis” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “reducing level of a protein….”, "enhances the binding", “reduce the level of the protein”, “ameliorate the Huntington’s disease….” or “attenuates the apoptosis”. It is unclear what the claimed enhancing the binding or the reduced level of the protein or the amelioration of HD defects or attenuation of the apoptosis is relative to. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as “a compound that enhances the binding” or “a compound that can reduce the level of the protein” or “a compound that attenuates the apoptosis” recited in the claims. Thus, the claims are indefinite.
ii. It is unclear whether the limitation “a compound” in “selecting a compound….” recited in the step (II), and step (i)/(ii) recited in claims 1, 7, 9-10, 32, 35-36, 38-41 is referred to any compound or the candidate compound that have been tested in step (I) and step (II) respectively. Thus the claims are indefinite.
iii. It is unclear what protein the limitation “the protein” recited in line 3 of step (i) recited in claim 1 or in the last line of claim 10, claim 39 is referred to. Thus, the claims are indefinite.
iv. The rest of claims are indefinite as depending from an indefinite claim.
Accordingly, the rejection of claims 1-2, 5-10, 20 and 32-40 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is maintained.
Claim Rejections - 35 USC § 112
8. 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 1-2, 5-10, 20 and 32-40 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 screening and identifying compounds 1 (GW5074), 2 (ispinesib), 3 (PubChem CID 1759437) and 4 (PubChem CID 5398649) based on their binding affinity to HTTexon1-Q72-MBP (SEQ ID NO:1) and LC3B (SEQ ID NO:8) and not binding to HTTexon1-Q25-MBP (SEQ ID NO: 5); and wherein the compounds 1, 2, 3 and 4 can reduce levels of mutant HTT (mHTT) in cortical neurons of HTT-Q140 knock-in heterozygous mice (Q140/Q7), in the fibroblasts (Q49, Q55, Q68) of HD patients, in iPSC-derived neurons derived from HD patient (Q47), in transgenic Drosophilae expressing human HTT full-length protein (Q128), in HD Model Mice expressing human Q140/Q7 but not levels of LC3B and other autophage proteins, and can enhance the binding between HTTexon1-Q72-MBP (SESQ ID NO:1) and LC3B (SEQ ID NO:8) but not between HTTexon1-Q25-MBP (SEQ ID NO:5) and LC3B (SEQ ID NO:8) or between flHTT-Q73 and LCB (SEQ ID NO:8) and their co-localization in cells, does not reasonably provide enablement for a method for screening or identifying a compound for reducing level of a protein with abnormally expanded polyQ in a cell, a tissue, an organ, or an animal or a method for screening or identifying a compound for treating Huntington’s disease comprising the steps recited in instant claims as broadly claimed. 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. The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1-2, 5-10 and 20 as amended are drawn to a method for screening or identifying a compound for reducing level of a protein with abnormally expanded polyQ in a cell, a tissue, an organ or an animal, comprising: steps (I) and (II):
(I): contacting a candidate compound with a test system comprising: protein (1) and protein (2);
(II): determining ability of the candidate compound to modulate the binding between protein (1) and protein (2); and selecting a compound that enhances the binding; and the method further comprises: step(i) or step (ii):
(i): determining an effect of the candidate compound on a level of the claimed protein with abnormally expanded polyQ in the cell, the tissue, the organ or the animal and selecting a compound that can reduce the level of the protein;
(ii): determining an effect of the candidate compound on subcellular localization of the claimed protein with abnormally expanded polyQ in a cell, and selecting a compound that can promote the protein with abnormally expanded polyQ to localize to autophagosomes;
wherein in steps (I) and (II), protein (2) is a LC3B protein with an amino acid sequence as shown in SEQ ID NO:3; and the protein with abnormally expanded polyQ is ATXN1 with 92 glutamine repeats (ATXN1-polyQ92) and protein (1) is ATXN1-polyQ92 or the protein with abnormally expanded polyQ is ATXN3 with 74 or 68 glutamine repeats (ATXN3-polyQ74 or ATXN3-polyQ68) and protein (1) is ATXN3-polyQ74 or ATXN3-polyQ68, o the protein with abnormally expanded polyQ is huntingtin (HTT) with 47, 49, 55, 68, 72, 73, 111, 128 or 140 glutamine repeats (HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140) or HTTexon1 with 72 glutamine repeats (HTTexon1-polyQ72).
Claims 32-40 are drawn to a method for screening or identifying a compound for treating Huntington’s disease (HD), comprising: steps (I), (II) and (III):
(I): contacting a candidate compound with a test system comprising: protein (1) and protein (2);
(II): determining ability of the candidate compound to modulate the binding between protein (1) and protein (2); and selecting a compound that enhances the binding;
(III): determining effect of the candidate compound on HD related behavioral defects in HD model mice; and selecting a compound that ameliorates the HD related behavioral defects in HD model mice;
wherein in steps (I) and (II), protein (2) is a LC3B protein with an amino acid sequence as shown in SEQ ID NO:8, and protein (1) is HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140 or HTTexon1-polyQ72.
Response to Arguments
On p. 13-14 of the response, Applicant argues that i) the rejection has been overcome in view of amendment to the claims; ii) Applicant new claims 32-42 are drawn to a method for screening or identifying a compound for treating HTT and HD model mice are reliable models of HD for testing therapeutic approaches and HD related behavioral defects are well-established indicators of HD and treatment of HD and cites A Physician’s Guide to the Management of Huntington’s Disease in support of the arguments.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2164, MPEP §§2164.01-2164.06(b) & 2164.08, the specification provides insufficient guidance to enable a skilled artisan to practice the full scope of the claimed invention without undue experimentation because:
i. There is no well-established structural and functional relationship or correlation between a LC3B protein comprising the amino acid sequence of instant SEQ ID NO:8 and a LC3B protein with an amino acid sequence as shown in SEQ ID NO:8 (which encompasses fragments within SEQ ID NO:8).
There is no well-established structural and functional relationship or correlation between the binding of “HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140 to fragments within SEQ ID NO:8, and the binding of HTTexon1-Q72-MBP (SEQ ID NO:1) to LC3B (SEQ ID NO:8) without binding to HTTexon1-Q25-MBP (SEQ ID NO: 5) in reducing the level of HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140 or in reducing levels of ATXN1-polyQ92, ATXN3-polyQ74 or ATXN3-polyQ68.
There is no well-established structural and functional relationship or correlation among the binding of HTTexon1-Q72-MBP (SEQ ID NO:1) to LC3B (SEQ ID NO:8) without binding to HTTexon1-Q25-MBP (SEQ ID NO: 5), reducing the levels of “HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140” and “treating Huntington’s disease”.
The examples shown in the specification to identify compounds 1-4 based on the binding of the compounds 1-4 to HTTexon1-Q72-MBP (SEQ ID NO:1) and LC3B (SEQ ID NO:8), but not binding to HTTexon1-Q25-MBP (SEQ ID NO: 5) and further characterize the activities or effects of compounds on reducing levels of mutant HTT (mHTT).
However, the specification provides no well-established structural and functional relationship or correlation between the screening using other mHTTs binding to LC3B of SEQ ID NO:8 or fragments thereof, and the screening based on binding to HTTexon1-Q72-MBP (SEQ ID NO:1) and LC3B (SEQ ID NO:8) but not binding to HTTexon1-Q25-MBP (SEQ ID NO: 5). Thus, it is unpredictable whether the results obtained from using the binding to HTTexon1-Q72-MBP (SEQ ID NO:1) and LC3B (SEQ ID NO:8) but not binding to HTTexon1-Q25-MBP (SEQ ID NO: 5) are applicable to the screening using other mHTTs binding to LC3B of SEQ ID NO:8 or fragments thereof.
ii. The specification only showed that:
1) identifying compounds 1 (GW5074), 2 (ispinesib), 3 (PubChem CID 1759437) and 4 (PubChem CID 5398649) based on their binding affinity to HTTexon1-Q72-MBP (SEQ ID NO:1) and LC3B (SEQ ID NO:8), but not binding to HTTexon1-Q25-MBP (SEQ ID NO: 5);
2) confirming that compounds 1, 2, 3 and 4 can reduce levels of mutant HTT (mHTT) in cortical neurons of HTT-Q140 knock-in heterozygous mice (Q140/Q7) (Example 2), in the fibroblasts (Q49, Q55, Q68) of HD patients (Example 3), in iPSC-derived neurons derived from HD patient (Q47) (example 4), in transgenic Drosophilae expressing human HTT full-length protein (Q128) (Example 5), in HD Model Mice expressing human Q140/Q7 (Example 6) but no effect on levels of LC3B and other autophage proteins (Example 7); and can enhance binding between HTTexon1-Q72-MBP (SESQ ID NO:1) and LC3B (SEQ ID NO:8) but not between HTTexon1-Q25-MBP (SEQ ID NO:5) and LC3B (SEQ ID NO:8) or between flHTT-Q73 and LC3B (SEQ ID NO:8) and their co-localization in cells (Examples 8-9);
3) confirming that compounds 1 and 4 can bind to Q72-GFP, Q53-GFP, Q46-GFP or Q38-GFP and reduce levels of Q72-GFP, Q53-GFP, Q46-GFP or Q38-GFP but not Q25-GFP (SEQ ID NO: 6) in cells transfected with these constructs (Examples 10-11);
4) confirming that compounds 1,3 and 4 can bind to MBP-ATXN3-Q68 but not MBP-ATXN3-Q28 (Example 12) and decrease levels of mutant ATXN3 in fibroblasts of SCA3 patient (Q74) but not in wild-type ATXN3 (Example 13); and
5) confirming that compounds 1, 2, 3 and 4 can bind to His-ATXN1-Q92 (Example 14) and decrease levels of mutant ATXN1 in fibroblasts of SCA1 patient (Q92) by compound 1,2,3,4, 6 or 7 (Example 15).
iii. The specification provides no well-established structural and functional relationship or correlation between the LC3B protein of SEQ ID NO:8 and a LC3B protein with an amino acid sequence as shown in SEQ ID NO:8 including fragments within SEQ ID NO:8).
The specification provides no well-established structural and functional relationship or correlation between the binding of HTTexon1-Q72-MBP (SEQ ID NO:1) to LC3B (SEQ ID NO:8) without binding to HTTexon1-Q25-MBP (SEQ ID NO: 5) and the binding of “HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140 to fragments within SEQ ID NO:8 in reducing the level of HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140 or in reducing levels of ATXN1-polyQ92, ATXN3-polyQ74 or ATXN3-polyQ68 or treating HD.
It is not known whether the results obtained from using the binding to HTTexon1-Q72-MBP (SEQ ID NO:1) and LC3B (SEQ ID NO:8) but not binding to HTTexon1-Q25-MBP (SEQ ID NO: 5) shown in examples of the instant specification are applicable to the screening using other mHTTs binding to LC3B of SEQ ID NO:8 or fragments thereof, indicating undue experimentation is required by a skilled artisan to perform while practicing the claimed methods.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by a skilled artisan to perform in order to practice the claimed invention as it pertains to a method for screening for a compound for reducing recited protein with abnormally expanded polyQ proteins or treating HD based on recited steps.
According, the rejection of claims 1-2, 5-10, 20 and 32-40 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, lack of scope of enablement is maintained.
Claim Rejections - 35 USC § 112
9. Claims 1-2, 5-10, 20 and 32-40 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1-2, 5-10, 20 and 32-40 as amended encompass using a genus of LC3B protein with an amino acid sequence as shown in SEQ ID NO:8 including fragments within SEQ ID NO:8 for identifying a compound that reduces the levels of recited proteins with abnormally expanded polyQ or treatment of HD.
Applicant has not disclosed sufficient species for using the broad genus of LC3B protein with an amino acid sequence as shown in SEQ ID NO:8 for identifying a compound for reducing the levels of the recited proteins with abnormally expanded polyQ or treatment of HD.
Response to Arguments
On p. 16 of the response, Applicant argues that the rejection has been overcome in view of amendment to the claims.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2163, MPEP §§2163.01-2163.03, the specification fails to provide sufficient description or information or evidence to demonstrate that Applicant is in possession of the claimed method by using the claimed genus of LC3B protein with an amino acid sequence as shown in SEQ ID NO:8 including fragments within SEQ ID NO:8 for identifying a compound that reduces the levels of recited proteins with abnormally expanded polyQ or treatment of HD because:
i. There is no well-established structural and functional relationship or correlation between a LC3B protein comprising the amino acid sequence of instant SEQ ID NO:8 and a LC3B protein with an amino acid sequence as shown in SEQ ID NO:8 (which encompasses fragments within SEQ ID NO:8).
There is no well-established structural and functional relationship or correlation between the binding of “HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140 to fragments within SEQ ID NO:8, and the binding of HTTexon1-Q72-MBP (SEQ ID NO:1) to LC3B (SEQ ID NO:8) without binding to HTTexon1-Q25-MBP (SEQ ID NO: 5) in reducing the level of HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140 or in reducing levels of ATXN1-polyQ92, ATXN3-polyQ74 or ATXN3-polyQ68.
There is no well-established structural and functional relationship or correlation among the binding of HTTexon1-Q72-MBP (SEQ ID NO:1) to LC3B (SEQ ID NO:8) without binding to HTTexon1-Q25-MBP (SEQ ID NO: 5), reducing the levels of “HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140” and “treating Huntington’s disease”.
ii. The experimental results described in the specification consist primarily of identifying compounds 1-4 that are capable of binding to HTTexon1-Q72-MBP (SEQ ID NO:1) and LC3B (SEQ ID NO:8), but not binding to HTTexon1-Q25-MBP (SEQ ID NO: 5) and characterizing the activities of the above identified compounds in reducing levels of mutant HTT (mHTT) in cortical neurons of HTT-Q140 knock-in heterozygous mice (Q140/Q7), in the fibroblasts (HTT-Q49, Q55, Q68) of HD patients, in iPSC-derived neurons derived from HD patient (HTT-Q47), in transgenic Drosophilae expressing human HTT full-length protein (HTT-Q128) and in enhancing binding between HTTexon1-Q72-MBP (SESQ ID NO:1) and LC3B (SEQ ID NO:8) but not between HTTexon1-Q25-MBP (SEQ ID NO:5) and LC3B (SEQ ID NO:8) or between flHTT-Q73 and LCB (SEQ ID NO:8) and their co-localization in cells.
iii. The specification provides no well-established structural and functional relationship or correlation between the binding of HTTexon1-Q72-MBP (SEQ ID NO:1) to LC3B (SEQ ID NO:8) without binding to HTTexon1-Q25-MBP (SEQ ID NO: 5) and the binding of “HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140 to fragments within SEQ ID NO:8 in reducing the level of HTT-polyQ47, HTT-polyQ49, HTT-polyQ55, HTT-polyQ68, HTT-polyQ72, HTT-polyQ73, HTT-polyQ111, HTT-polyQ128 or HTT-polyQ140 or in reducing levels of ATXN1-polyQ92, ATXN3-polyQ74 or ATXN3-polyQ68 or treating HD.
Since the common characteristics/features of the broad genus of LC3B protein with an amino acid sequence as shown in SEQ ID NO:8 including fragments within SEQ ID NO:8 for identifying a compound that reduces the levels of recited proteins with abnormally expanded polyQ or treatment of HD are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention in view of Burgess et al. (J of Cell Bio. 1990, 111:2129-2138, cited previously), Bowie et al. (see col 2, p. 1306, Bowie et al. Science, 1990, 247:1306-1310, cited previously), Pawson et al. (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452, cited previously), Alaoui-lsmaili et al. (see p. 502, right col., 2th paragraph; Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507, cited previously) and Guo et al. (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210, cited previously).
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of using the genus of LC3B protein with an amino acid sequence as shown in SEQ ID NO:8 including fragments within SEQ ID NO:8 for identifying a compound that reduces the levels of recited proteins with abnormally expanded polyQ or treatment of HD.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of LC3B protein with an amino acid sequence as shown in SEQ ID NO:8 including fragments within SEQ ID NO:8 for identifying a compound that reduces the levels of recited proteins with abnormally expanded polyQ or treatment of HD, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 and Centocor v. Abbott, 636 F.3d1341 (Fed. Cir. 2011) and AbbVie v. Janssen, 759 F.3d 1285 (Fed. Cir.2014). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed method has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
Accordingly, the rejection of claims 1-2, 5-10, 20 and 32-40 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 is maintained.
Conclusion
10. NO CLAIM IS ALLOWED.
11. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
WO2012004778 teaches a novel ex-vivo method for assaying a neuroactive substance and for monitoring early neuronal disease-related changes in neuronal network behavior comprising a neuronal cell culture comprising genetically engineered neurons to express at least one neurogenerative active protein including SEQ ID NO:2 which is 93.2% identical to instant SEQ ID NO:1 (see sequence alignment below).
SEQ ID NO:1
AZS27122
ID AZS27122 standard; protein; 256 AA.
XX
AC AZS27122;
XX
DT 01-MAR-2012 (first entry)
XX
DE Human htt171-82Q-linker-myc tag-6X His tag mutant protein, SEQ:2.
XX
KW HD protein; Huntingtin; alzheimers disease; antiparkinsonian;
KW frontotemporal dementia; genetic-disease-gen.; growth-disorder-gen.;
KW htt protein; huntingtons chorea; lewy body dementia;
KW motor neurone disease; mutein; neurodegenerative disease; neuron;
KW neuroprotective; nootropic; parkinsons disease; prognosis;
KW prophylactic to disease; protein therapy; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 1..171
FT /note= "Huntingtin protein"
FT Region 18..99
FT /note= "Glutamine (Q) repeats"
FT Region 236..245
FT /note= "Myc tag"
FT Region 251..256
FT /note= "His tag"
XX
CC PN WO2012004778-A1.
XX
CC PD 12-JAN-2012.
XX
CC PF 11-JUL-2011; 2011WO-IB053073.
XX
PR 09-JUL-2010; 2010CH-00001124.
XX
CC PA (EPFL ) ECOLE POLYTECHNIQUE FEDERALE LAUSANNE.
XX
CC PI Giugliano M, Luthi-Carter R, Markram H, Gambazzi L, Goekce O;
XX
DR WPI; 2012-A62554/06.
DR N-PSDB; AZS27134.
XX
CC PT Assaying neuroactive substance ex-vivo comprises providing neuronal cell
CC PT culture sample comprising genetically engineered neuronal cell, comparing
CC PT electrophysiological response parameters, determining difference in
CC PT parameters and detecting.
XX
CC PS Claim 4; SEQ ID NO 2; 60pp; English.
XX
CC The present invention relates to a novel ex-vivo method for assaying a
CC neuroactive substance and for monitoring early neuronal disease-related
CC changes in neuronal network behaviour. The ex-vivo method comprises (a)
CC providing a neuronal cell culture sample comprising genetically
CC engineered neuronal cells wherein neuronal cells are genetically
CC engineered to express at least one neurodegenerative active protein; (b)
CC comparing at least one electrophysiological response parameter measured
CC simultaneously at a plurality of regions in the neuronal cell culture
CC sample when contacted with a candidate substance or a candidate substance
CC composition with a baseline electrophysiological response parameter of
CC the regions; (c) determining the difference between the
CC electrophysiological response parameter and the baseline
CC electrophysiological response parameter; (d) detecting the presence or
CC absence of a neuroactive substance in the candidate substance or a
CC candidate substance composition based upon the difference determined
CC under step (c) and/or detecting a neuronal adverse effect of the
CC candidate substance or candidate substance composition based upon the
CC difference determined under step (c). The invention independently claims
CC for a kit of electrophysiological detection of the neuroactive substance,
CC which comprises the genetically engineered neuronal cells or the
CC composition or neuronal cells together with vectors to genetically
CC engineer neuronal cells, where the genetically engineered neuronal cells
CC or the neuronal cells once transduced with the vectors express a
CC neurodegenerative active protein. The neuroactive substance is used to
CC prevent, repress or treat neuronal dysfunctions such as Alzheimer's
CC disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal
CC dementia, Huntington's disease and amyotrophic lateral sclerosis. The
CC present sequence represents a human huntingtin (htt)171-82Q-linker-myc
CC tag-6X His tag mutant protein, which is the neurodegenerative active
CC protein expressed by the neuronal cell in the ex-vivo method for assaying
CC the neuroactive substance.
XX
SQ Sequence 256 AA;
Query Match 98.0%; Score 726; Length 256;
Best Local Similarity 93.2%;
Matches 138; Conservative 0; Mismatches 0; Indels 10; Gaps 1;
Qy 1 MATLEKLMKAFESLKSF----------QQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ 50
||||||||||||||||| |||||||||||||||||||||||||||||||||
Db 1 MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ 60
Qy 51 QQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQ 110
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQ 120
Qy 111 PLLPQPQPPPPPPPPPPGPAVAEEPLHR 138
||||||||||||||||||||||||||||
Db 121 PLLPQPQPPPPPPPPPPGPAVAEEPLHR 148
WO2018226776 teaches an autophagosome maturation assay vector comprising nucleotide sequence encoding autophagy-related 8 family protein operably linked to nucleotide sequence encoding haloalkane dehalogenase used in autophagosome
maturation assay, wherein the autophagy-related 8 family protein comprises the amino acid sequence of SEQ ID NO:2, which is 100% identical to instant SEQ ID NO:8 (see the sequence alignment below).
SEQ ID NO:8
BFX11399
ID BFX11399 standard; protein; 445 AA.
XX
AC BFX11399;
XX
DT 07-FEB-2019 (first entry)
XX
DE Autophagosome maturation assay vector encoded protein, SEQ ID 2.
XX
KW Haloalkane dehalogenase; LC3B protein;
KW Microtubule-associated protein 1 light chain 3B;
KW Microtubule-associated protein light chain 3B; antiinflammatory;
KW autophagosome; brain disease; breast tumor; cancer; colorectal tumor;
KW crohns disease; cytostatic; dermatological; drug screening;
KW gastrointestinal-gen.; hematological neoplasm; immunosuppressive;
KW lipidosis; liver tumor; metabolic-gen.; musculoskeletal-gen.;
KW neurodegenerative disease; neuroprotective; ovary tumor;
KW parkinsons disease; prostate tumor; screening;
KW systemic lupus erythematosus; therapeutic; vector.
XX
OS Tobacco etch virus.
OS Mammalia.
OS Chimeric.
OS Synthetic.
OS Unidentified.
XX
CC PN WO2018226776-A1.
XX
CC PD 13-DEC-2018.
XX
CC PF 06-JUN-2018; 2018WO-US036184.
XX
PR 08-JUN-2017; 2017US-0516756P.
XX
CC PA (PSRF ) PENN STATE RES FOUND.
XX
CC PI Takahashi Y, Wang H;
XX
DR WPI; 2018-99598M/01.
DR N-PSDB; BFX11398.
XX
CC PT New autophagosome maturation assay vector comprising nucleotide sequence
CC PT encoding autophagy-related 8 family protein operably linked to nucleotide
CC PT sequence encoding haloalkane dehalogenase used in autophagosome
CC PT maturation assay.
XX
CC PS Claim 3; SEQ ID NO 2; 94pp; English.
XX
CC The present invention relates to a novel autophagosome maturation assay
CC vector comprising a nucleotide sequence of SEQ ID NO: 1 (see BFX11398).
CC The autophagosome maturation assay vector comprises a nucleotide sequence
CC encoding an autophagy-related 8 (Atg8) family protein operably linked to
CC a nucleotide sequence encoding a haloalkane dehalogenase (Halo Tag). The
CC Atg8 family protein can be selected from gamma-aminobutyric acid receptor
CC -associated protein (GABARAP), gamma-aminobutyric acid receptor-
CC associated like protein (GABARAPL1), golgi-associated ATPase enhancer of
CC 16 kDa (GATE-16), microtubule-associated protein light chain 3A (LC3A),
CC microtubule-associated protein light chain 3B (LC3B), microtubule-
CC associated protein light chain 3B2 (LC3B2) and microtubule-associated
CC protein light chain 3C (LC3C), where LC3 is a mammalian ortholog of yeast
CC Atg8. The invention further claims: (1) a cell comprising the
CC autophagosome maturation assay vector; (2) an autophagosome maturation
CC assay that provides superior signal-to-noise ratio and high
CC reproducibility to distinguish phagophores, nascent autophagosomes and
CC mature autophagosomal structures; (3) a method of screening for the
CC effect of a compound on the closure of autophagosomes or the progression
CC of the lysosomal-dependent catabolic pathway; and (4) a method for
CC treating a disease or disorder associated with a deficiency in the
CC closure of autophagosomes or the progression of the lysosomal dependent
CC catabolic pathway in a subject. The vector of the present invention is
CC useful in an autophagosome maturation assay. The methods are useful for
CC screening for the effect of a compound on the closure of autophagosomes
CC or the progression of the lysosomal-dependent catabolic pathway and for
CC treating Crohn's disease, Vici syndrome, cancer (such as breast cancer,
CC ovarian cancer, prostate cancer, liver cancer, colorectal cancer and
CC hematologic cancer), systemic lupus erythematosus and neurodegenerative
CC diseases such as static encephalopathy of childhood with
CC neurodegeneration in adulthood (SENDA), Parkinson's disease and
CC phospholipidosis. The present sequence represents an autophagosome
CC maturation assay vector (comprising a LC3B gene, a TEV sequence and a
CC Halo Tag coding DNA) encoded protein, whose coding DNA can be used in an
CC autophagosome maturation assay.
XX
SQ Sequence 445 AA;
Query Match 100.0%; Score 631; Length 445;
Best Local Similarity 100.0%;
Matches 125; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MPSEKTFKQRRTFEQRVEDVRLIREQHPTKIPVIIERYKGEKQLPVLDKTKFLVPDHVNM 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 321 MPSEKTFKQRRTFEQRVEDVRLIREQHPTKIPVIIERYKGEKQLPVLDKTKFLVPDHVNM 380
Qy 61 SELIKIIRRRLQLNANQAFFLLVNGHSMVSVSTPISEVYESEKDEDGFLYMVYASQETFG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 381 SELIKIIRRRLQLNANQAFFLLVNGHSMVSVSTPISEVYESEKDEDGFLYMVYASQETFG 440
Qy 121 MKLSV 125
|||||
Db 441 MKLSV 445
Krainc et al. (US9284366, issued Mar 15, 2016, priority Nov 2, 2006) teach methods of preparing acetylated Huntingtin (Htt) polypeptides, acetylated Htt polypeptide antigens, and antibodies that specifically recognize acetylated epitopes on Htt polypeptides or antibodies that specifically recognize and bind to acetylated epitopes on acetylated Htt polypeptides wherein the acetylated Htt polypeptides comprises an acetylated lysine corresponding to K444 residue of full-length, wild-type Htt polypeptide (see abstract; col. 39-43). Krainc teaches Neuro2a cells or immortalized striatal cells (STHdhQ7/Q7) transfected with Htt590-97Q and treated with the proteasome inhibitor lactacystin or autophagy inhibitor 3-methyladenine (3-MA), wherein acetylation of mutant Htt leads to increased LC3-I to LC3-II conversion (See col. 8, lines 28-43; col. 42, lines 38-col.42, line 44) or COS-7 cells transfected with Htt480-68Q-RFP or Htt480-68Q-KR-RFP together with GFP-LC3 and CBP-HAT (col. 42, lines 29-44).
Yano et al. (US10842807, issued Nov 24, 2020, priority Jun 13, 2016) teaches a method to reduce symptoms associated with Huntington’s disease (HD) in a subject in need thereof or reduce mutant Huntingtin (Htt)-induced neurotoxicity, comprising administering to the subject a DNA methylation inhibitor, wherein the DNA methylation inhibitor is a nucleoside analog DNA methyltransferase (DNMT) inhibitor and wherein the DNMT inhibitor decreases the levels of mutant Htt aggregates (see col. claims 1-11).
Qi (US10143719, issued Dec 4, 2018, priority Feb 6, 2015) teaches methods of inhibiting valosin-containing protein (VCP) accumulation in mitochondria of a nerve cell or treating Huntington’s disease in a subject in need thereof, the method comprising: administering to the nerve cell or the subject a therapeutic peptide having the amino acid sequence of SEQ ID NO: 3 or peptide HV-3 (derived from Htt-C-terminal) to block the interaction between Htt and VCP (see abstract; col.29-36, claims 1-9).
Xie et al. (US10759739, issued Sep 1, 2020, priority Jun 11, 2015) teaches p62-ZZ inhibitors having a formula I (see abstract; col. 1-4; claims 1-18). Xie teaches that Sequestosome-1 (SQSTM1/p62) is rich with protein-interacting domains, including an N-terminal PB1 domain, a ZZ-type zinc finger domain, a TRAF6-binding domain (TBS), the LC3-interacting region (LIR), the KEAP1-interacting region (KIR), and a C-terminal ubiquitin binding domain (UBA) and is involved in accumulation of aggregated mutant Huntingtin protein (see col. 1-2).
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
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Chang-Yu Wang
September 5, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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