DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 7, 2026 has been entered.
Claims 1-14, 16-18, 20-24, and 31-35 have been canceled.
Claims 15, 19, 25-30, and 36-47 are pending.
Claims 19, 26-30, 36-45, and 47 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 28, 2025.
Claims 15, 25, and 46 are currently under consideration as they read on the elected invention of a method of improving blood-brain barrier function and the species of autoimmune encephalitis.
3. In view of applicant’s amendment, following rejection are set forth.
4. 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.
5. Claims 15, 25, and 46 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.
The claims are indefinite in the recitation of “selecting an antibody that specially binds human IL-6 receptor and has been shown to be effective in restoring blood-brain barrier function in an in vitro model….; wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:10 and a light chain comprising the amino acid sequence of SEQ ID NO:9” because the metes and bounds of “selecting an antibody” is ambiguous. Given that the administered antibody comprises the heavy chain of SEQ ID NO:10 and light chain of SEQ ID NO:9, it is not clear if the selecting step recited in independent claim 15(ii) is a method step required by the claims. Further, it is also not clear if the limitation of “has been shown to be effective in restoring blood-brain barrier function in an in vitro model” is a method step required by the claim or merely a statement of the features of the antibody.
6. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
7. 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
8. Claims 15, 25, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Dale (Neurotherapeutics, 2016, 13:821-823) in view of Igawa et al. (US 2010/0298542) and Blecharz-Lang et al. (Translational Stroke Research 2018, 9:631-642).
Dale teaches that autoimmune encephalitis is a group of inflammatory brain conditions defined by the presence of autoantibodies against cell-surface proteins such as neuronal receptors or synaptic protein and teaches diagnostic criteria for AE (e.g. see lines 1-10 in left col. in page 821). Therefore, Dale teaches identifying a subject as having a condition including autoimmune encephalitis. While Dale does not teach that autoimmune disease characterized by reduced blood-brain barrier function as recited in claim 15(1), such recitation merely characterized the AE rather than providing a real method step. As such, Dale teaches diagnostic criteria of AE and treating AE, thus, Dale also teaches identifying AE patient.
Dale (Neurotherapeutics, 2016, 13:821-823) teaches that IL-6 blocker Tocilizumab is effective in treating human AE patients who have failed to respond to rituximab (e.g. see right col. in page 821). Dale teaches that the patients in tocilizumab group did significantly better than the patients in both rituximab and observation group at 1 month, 2 months, and final follow-up, and the safety profile of tocilizumab is reasonable with no reported infusion reactions (e.g. see right col. in page 821). Therefore, Dale teaches selecting anti-human IL-6 receptor antibody in instant claim 15(2).
The reference teachings differ from the instant invention by not teaching the particular anti-human IL6R antibody comprising a heavy chain of SEQ ID NO:10 and a light chain of SEQ ID NO:9.
However, the anti-IL6R antibody comprising heavy chain of SEQ ID NO:10 and a light chain of SEQ ID NO:9 was well known in the art at the time the invention was filed. For example, Igawa et al. teach an anti-human IL-6R antibody having identical amino acid sequences as the full length of the instantly claimed antibody including identical CDRs, VH, and VL, see alignments below:
Instant heavy chain SEQ ID NO:10 (Qy) alignment to the prior art SEQ ID NO:46 (Db):
RESULT 1
US-12-680-082-46
(NOTE: this sequence has 25 duplicates in the database searched.
See complete list at the end of this report)
Sequence 46, US/12680082
Patent No. 9688762
GENERAL INFORMATION
APPLICANT: CHUGAI SEIYAKU KABUSHIKI KAISHA
TITLE OF INVENTION: Modified antibody constant region
FILE REFERENCE: 14875-0206US1 / C1-A0709P
CURRENT APPLICATION NUMBER: US/12/680,082
CURRENT FILING DATE: 2010-03-25
PRIOR APPLICATION NUMBER: JP 2007-250147
PRIOR FILING DATE: 2007-09-26
NUMBER OF SEQ ID NOS: 58
SEQ ID NO 46
LENGTH: 443
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: An artificially synthesized peptide sequence
Query Match 100.0%; Score 2363; Length 443;
Best Local Similarity 100.0%;
Matches 443; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGPGLVKPSETLSLTCAVSGHSISHDHAWSWVRQPPGEGLEWIGFISYSGITNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGPGLVKPSETLSLTCAVSGHSISHDHAWSWVRQPPGEGLEWIGFISYSGITNY 60
Qy 61 NPSLQGRVTISRDNSKNTLYLQMNSLRAEDTAVYYCARSLARTTAMDYWGEGTLVTVSSA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NPSLQGRVTISRDNSKNTLYLQMNSLRAEDTAVYYCARSLARTTAMDYWGEGTLVTVSSA 120
Qy 121 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 180
Qy 181 LYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPAPPVAGPSVFL 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPAPPVAGPSVFL 240
Qy 241 FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRV 300
Qy 301 VSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSQEEMTKNQ 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSQEEMTKNQ 360
Qy 361 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQEGNV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQEGNV 420
Qy 421 FSCSVMHEALHAHYTQKSLSLSP 443
|||||||||||||||||||||||
Db 421 FSCSVMHEALHAHYTQKSLSLSP 443
Instant light chain of SEQ ID NO:9 (Qy) alignment to the prior art light chain (Db):
RESULT 1
US-12-680-082-47
(NOTE: this sequence has 39 duplicates in the database searched.
See complete list at the end of this report)
Sequence 47, US/12680082
Patent No. 9688762
GENERAL INFORMATION
APPLICANT: CHUGAI SEIYAKU KABUSHIKI KAISHA
TITLE OF INVENTION: Modified antibody constant region
FILE REFERENCE: 14875-0206US1 / C1-A0709P
CURRENT APPLICATION NUMBER: US/12/680,082
CURRENT FILING DATE: 2010-03-25
PRIOR APPLICATION NUMBER: JP 2007-250147
PRIOR FILING DATE: 2007-09-26
NUMBER OF SEQ ID NOS: 58
SEQ ID NO 47
LENGTH: 214
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: An artificially synthesized peptide sequence
Query Match 100.0%; Score 1111; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDSVTITCQASTDISSHLNWYQQKPGKAPELLIYYGSHLLSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDSVTITCQASTDISSHLNWYQQKPGKAPELLIYYGSHLLSGVPS 60
Qy 61 RFSGSGSGTDFTFTISSLEAEDAATYYCGQGNRLPYTFGQGTKVEIERTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTFTISSLEAEDAATYYCGQGNRLPYTFGQGTKVEIERTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Igawa et al. teach that the humanized anti-IL-6 receptor antibody has improved PK/PD and higher antigen binding affinity compared to Tocilizumab (e.g. see Example 11).
Blecharz-Lang et al. teach combined blood-brain barrier (BBB) by dysregulation of cellular junctions is a hallmark of many cerebrovascular disorders due to the pro-inflammatory cytokines action and IL-6 is implicated in inflammatory process and in secondary brain injury (e.g. see Abstract). Blecharz-Lang et al. teach that IL-6 is an essential inflammatory mediator and also serve as an important messenger molecule between the brain endothelial activation at the luminal side of the BBB and the cells of brain parenchyma (e.g. see left col. in page 632).
The reference further teaches IL-6 impaired ability to build intact tubes --- barrier characteristics of BBB-derived endothelial cells (ECs), representing essential EC functions (e.g. see right col. in page 635). Blecharz-Lang et al. teach that neutralizing anti-ILR antibody was able to attenuate the damaging effect of IL-6 in EC monolayer in vitro (e.g. see left col. in page 638).
Furthermore, Blechartz-Lang et al. teach that the blood brain barrier (BBB) is a tight cellular barrier between the blood and the central nervous system that was strictly regulated by brain endothelial cells (ECs) located at the inner surface of brain capillaries (e.g. see right col. in page 631). Blechartz-Lang et al. teach increased BBB permeability has been linked to inflammatory process at brain endothelium mediated by inflammatory cytokines including IL-6, e.g. see left col. in page 632. Blechartz-Lang et al. teach that the loss of essential inter-endothelial junction molecule (resulting in increased permeability of BBB) can be partially attenuated by the blocking anti-IL-6R antibody. Based on the in vitro data, the mechanism of neutralizing the IL-6R expressed by endothelial cells of cerebral origine can be considered as a potential strategy to reduce BBB disruption (e.g. see right col. in page 638).
It would thus be obvious to one of ordinary skill in the art at the time the invention was filed to simply select a well-known variant of the humanized anti-human IL-6R antibody with improved PK/PD and enhanced antigen binding disclosed in Igawa to replace the Tocilizumab used in the method of treating AE by Dale. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since Dale teaches that the humanized anti-IL-6R antibody Tocilizumab was selected to treat human patient identified suffering from AE by blocking IL-6 activity and thereby reduce disease activity and given the availability of an improved tocilizumab as disclosed by Igawa et al., an ordinary skill in the art would have been able to replace Tocilizimab with its improved variant with a reasonable expectation of success in treating AE in human.
Further, given that it was known in the art at the time the instant invention was filed that:
a) proinflammatory cytokine IL-6 is responsible for increasing the permeability of BBB and can be attenuated by blockade of IL-6 receptor expressed in brain microvascular ECs (as shown by Blechartz-Lang et al.),
b) anti-IL-6R antibody is effective in treating AE as disclosed by Dale, and
c) well-established in vitro methods of determining the neutralizing mechanism of an anti-IL-6R antibody as a potential strategy to reduce BBB disruption induced by the proinflammatory cytokine IL-6,
an ordinary skill in the art would have been motivated to determine the effectiveness of the anti-IL-6R antibody readily available from Igawa et al. following the well-established in vitro method described by Blechartz-Lang et al. in order to study the mechanism of the anti-IL-6R antibody already used to treat AE patients.
Given that Dale teaches that tocilizumab was effective in treating AE, and given the availability of an improved version of tocilizumab as disclosed in Igawa, an ordinary skill in the art would have been motivated to treat AE with the improved anti-IL6 receptor antibody disclosed in Igawa with a reasonable expectation of success. Further, given that the combined prior art teaches method of treating the same patient population suffering from AE by administering the same improved tocilizumab, the prior art method would have achieved the same result of improving blood-brain barrier function in AE patients without evidence to the contrary.
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant argues that claim 15 has been amended to recite the feature of the antibody being effective in improving blood brain barrier. Applicant asserts that none of the references cited by the examiner teach this feature. Applicant asserts that Dale states that there are number of questions about tocilizumab and its role in the treatment of AE, and one of the questions is weather tocilizumab acts peripherally or centrally within CNS. There are no teachings of affecting blood-brain barrier. Therefore, applicant asserts that one of skill in the art cannot derive from Dale or Igawa a reasonable expectation of either tocilizumab or any other anti-IL-6 antibody to have any effect in the brain of AE patients, much less improvement of BBB function.
Applicant asserts that the prior art does not teach step (ii) of claim 15, namely selecting an antibody that specifically binds humanIL-6 receptor and has been shown to be effective in restoring BBB function in an in vitro model of reduced BBB function.
Therefore, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for the reasons stated above. In addition, the recitation of “has been shown to be effective in restoring blood-brain barrier function in an in vitro model of reduced blood-brain barrier function” in instant claim 15(ii) appears to be reciting the feature of the anti-IL-6R antibody administered in claim 15 (iii) which has the identical amino acid sequences for the heavy and light chains as the one disclosed by Igawa. Given that the properties of a compound cannot be separated from the compound, see In re Papesch, 315 F.2d 381,391 (CCPA 1963) (“a compound and all its properties are inseparable), the prior art anti-IL-6R antibody having identical amino acid sequences as the instantly administered antibody would have the same properties, e.g. to be effective in restoring blood-brain barrier function in an in vitro model of reduced blood-brain barrier function.
9. No claim is allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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