DETAILED ACTION
The Art Unit location and the examiner of your application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1647, Examiner Bridget Bunner.
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 .
Status of Application, Amendments and/or Claims
The amendment of 12 November 2025 has been entered in full. Claims 22, 33, 52, 55, are amended. Claims 4-6, 8-10, 14, 17, 19, 21, 23-27, 29, 31, 32, 34, 36, 39, 40, 44, 46, 49, 51, 53, 54, 57-60, 63-68, and 70-74 are cancelled.
Claims 1-3, 7, 11-13, 15, 16, 18, 20, 22, 28, 30, 33, 35, 37, 38, 41-43, 45, 47, 48, 50, 52, 55, 56, 61, 62, and 69 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-3, 7, 11-13, 15, 16, 18, 20, 22, 28, 30, 47, 48, 50, 52, 55, 56, 61, 62, and 69, drawn to a method of treating acute or chronic respiratory distress syndrome, in the reply filed on 12 November 2025 is acknowledged.
Furthermore, Applicant’s election of the anti-IL-6 antibody species of (i) an antibody comprising variable light chain polypeptide CDRs of SEQ ID NO: 4, 5, and 6, and variable heavy chain polypeptide CDRs of SEQ ID NOs: 7, 8 or 120, and 9, in the reply filed on 12 November 2025 is also acknowledged.
Claims 33, 35, 37, 38, 41-43, and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 November 2025.
Claims 1-3, 7, 11-13, 15, 16, 18, 20, 22, 28, 30, 47, 48, 50, 52, 55, 56, 61, 62, and 69 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/18/26; 12/04/25; 11/24/25; 11/12/25; 08/27/27; 08/08/25; 04/03/25; 03/11/25; 02/06/25; 01/17/25; 11/08/24; 09/17/24; 07/03/24; 05/10/24; 11/08/23; 08/24/23; 08/14/23; 07/13/23; 03/31/23; 02/07/23 (6); and 09/15/22 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
1. The drawings are objected to because in Figures 2, 3, 4, and 5A-5D, the text is illegible due to the gray shading in the boxes and small font. It is suggested that the Figures are updated to (i) have white boxes, rather than gray ones and (ii) larger font size.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
2. Claim 69 is objected to because of the following informalities:
2a. In claim 69, subpart (e), line 2, there is a period after the phrase “is slowed”. This issue could be overcome by replacing the period with a comma or semi-colon.
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.
3. Claims 52, 56, and 62 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.
3a. Claim 52 recites the limitation "the patient" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 52 depends, does not recite “a patient”. Claim 1 recites “a subject”.
3b. Claim 56 recites the limitation "clazakizumab" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 56 depends, does not recite “clazakizumab”. Claim 1 only recites “an anti-human IL-6 antibody”.
3c. Claim 62 is rejected as being indefinite because lines 1-2 recite that the subject is further treated with a one or more specific agents (a)-(x). Claim 61, from which claim 62 depends, recites that the subject is administered at least one additional therapeutic comprising one or more of corticosteroids; inhaled NO; extracorporeal membrane oxygenation; or an immunosuppressive agent. Thus, it is not clear if the subject recited in claim 62 is administered one (or more) of (a)-(x) therapeutics in addition to those recited in claim 61. Or, do the therapeutics recited in claim 62 further limit the therapeutics recited in claim 61? The difference between an immunosuppressive agent (recited in claims 61 and 62, subpart (b)) and an immunosuppression regime (recited in claim 62, subpart (a)) is also not clear.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
4. Claims 1-3, 7, 11-13, 18, 61, 62, and 69 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Shailubhai et al. (US 2021/0284743 or WO 2021/180821; priority to 10 March 2020). It is noted that US 2021/0284743 and WO 2021/180821 have the same disclosure. Thus, for brevity, relevant portions of US 2021/0284743 will be cited below.
Shailubhai et al. indicate that IL-6 is a potent pleiotropic cytokine that regulates cell growth and differentiation and is an important mediator of acute inflammatory responses (page 1, [0005]). Shailubhai et al. continue to disclose that dysregulated IL-6 signaling has been implicated in the pathogenesis of many diseases, such as COVID-19 caused by coronavirus (page 1, [0005]). Shailubhai et al. teach a method of treating a symptom of a CRS (cytokine release syndrome), ARDS or a coronavirus infection in a subject in need thereof comprising administering to the subject a composition comprising an IL-6R antibody, meeting the limitations of instant claims 1, 3, 13, and 69 (page 18, [0207]; page 3, [0035]). Shailubhai et al. also teach that an example of IL-6/IL-6R antibodies useful in the methods of the disclosure include anti-IL-6 monoclonal antibodies, meeting the limitations of instant claim 1 (page 3, [0035], [0047]).
Shailubhai et al. disclose treatment of a disease or pathology associated with coronavirus infection in a subject (page 18, [0211]). Shailubhai et al. indicate that the subject has a disease or pathology associated with a pulmonary inflammatory disease, such as acute respiratory distress syndrome (ARDS) or pulmonary sclerosis (also known as, pulmonary fibrosis) (page 18, [0211]; page 19, [0216]; page 2, [0025]). Shailubhai et al. also disclose treatment of a symptom of ARDS associated with a coronavirus infection (page 3, [0037]). Shailubhai et al. state that the coronavirus infection is COVID-19, meeting the limitations of instant claim 2 (page 3, [0037-0038]). Shailubhai et al. do not teach subject has been intubated, meeting the limitations of instant claim 12. Shailubhai et al. teach that the subject is a human subject and that the subject has or is suspected of having a coronavirus infection, meeting the limitations of instant claims 1, 3, and 7 (page 19, [0216]; page 21, [0250]).
Shailubhai et al. disclose that the dosage regimen utilizing the therapeutic compounds includes daily administration, followed by at least one day, at least two days, at least three days, at least four days, at least five days, or at least six days, without administration, meeting the limitations of instant claim 18 (page 20, [0242]). Shailubhai et al. state that the dosing regimen can also be once or twice over a period of 1, 2, or 3 weeks (page 21, [0243]).
Shailubhai et al. teach the methods also comprise further administering to the subject a CD3 monoclonal antibody (which suppresses hyperactive immune responses), an antiviral drug, an immune booster drug, vitamin C, or vitamin D, meeting the limitations of instant claims 61 and 62, subpart (d) (page 2, [0015]; page 3, [0043, 0046]; page 17, [0196]).
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.
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.
5. Claims 1-3, 7, 11-13, 15, 16, 18, 20, 22, 28, 30, 47, 55, 61, 62, and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Shailubhai et al. (US 2021/0284743 or WO 2021/180821; priority to 10 March 2020) and Smith et al. (WO 2010/065072; cited on the IDS of 15 September 2022).
The teachings of Shailubhai et al. are set forth above.
Shailubhai et al. do not teach that the anti-IL-6 antibody is administered at a dose ranging from 10-25 mg or specific sequences for the anti-IL-6 antibody. Shailubhai et al. do not teach detecting CRP levels in a subject after treatment.
Smith et al. teach that the generation of an anti-IL6 antibody termed, “Ab1” (pages 268-271; pages 279-280, Example 13). Smith et al. disclose that the anti-IL6 antibody can be administered to treat diseases and disorders associated with cytokine storm, such as ARDS (page 251, [01231]). Smith et al. also indicate that the administered antibody lowers C-reactive protein (CRP) levels, which can be detected after antibody administration, meeting the limitations of instant claim 55 (page 1, [0003-0004]; page 4, [0014]; pages 282-283, Example 20; page 285-290, Examples 22-25).
Smith et al. disclose that the Ab1 antibody is humanized and comprises the variable heavy and light chain sequences of SEQ ID NO: 657 and 709 (page 12, [0046]; page 50, [0234-0235]). It is noted that the amino acid sequences of SEQ ID NOs; 657 and 709 of Smith et al. are 100% identical to the variable heavy and light chain sequences of SEQ ID NO: 657 and 709 of the instant application, meeting the limitations of instant claim 22 (see sequence alignments, below (with CDRs in bold)).
SEQ ID NO: 657
AYC86615 standard; protein; 120 AA.
AC AYC86615;
DT 05-AUG-2010 (first entry)
DE Humanized anti-interleukin-6 antibody heavy chain protein, SEQ ID 657.
KW IL6; Interleukin-6 ligand; acoustic neuroma;
KW acquired immune deficiency syndrome; allergy; alopecia areata; analgesic;
OS Oryctolagus cuniculus.
OS Homo sapiens.
OS Synthetic.
FH Key Location/Qualifiers
FT Region 30..34
FT /label= Complementarity_determining_region_1
FT Region 49..64
FT /label= Complementarity_determining_region_2
FT Region 95..106
FT /label= Complementarity_determining_region_3
CC PN WO2010065072-A1.
CC PD 10-JUN-2010.
CC PF 24-NOV-2009; 2009WO-US006257.
XX
PR 25-NOV-2008; 2008US-0117811P.
PR 25-NOV-2008; 2008US-0117839P.
PR 25-NOV-2008; 2008US-0117861P.
PR 05-FEB-2009; 2009US-00366567.
PR 24-FEB-2009; 2009US-00391615.
PR 24-FEB-2009; 2009US-00391717.
PR 06-MAR-2009; 2009US-00399156.
PR 14-JUL-2009; 2009US-00502581.
XX
CC PA (ALDE-) ALDEN BIOPHARMACEUTICALS INC.
XX
CC PI Smith JTL;
XX
DR WPI; 2010-G61183/41.
XX
CC PT Improving survivability or quality of life of patient involves
CC PT administering to patient interleukin-6 antagonist; and monitoring patient
CC PT to assess reduction of serum C-reactive protein level or increase serum
CC PT albumin level in the patient's.
XX
CC PS Claim 33; SEQ ID NO 657; 433pp; English.
SQ Sequence 120 AA;
Qy=instant SEQ ID NO: 657
Db=SEQ ID NO: 657 of Smith et al.
Query Match 100.0%; Score 629; DB 1; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYVTWVRQAPGKGLEWVGIIYGSDETAYA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYVTWVRQAPGKGLEWVGIIYGSDETAYA 60
Qy 61 TSAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDSSDWDAKFNLWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TSAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDSSDWDAKFNLWGQGTLVTVSS 120
SEQ ID NO: 709
ID AYC86667 standard; protein; 111 AA.
XX
AC AYC86667;
XX
DT 05-AUG-2010 (first entry)
XX
DE Rabbit anti-interleukin-6 antibody VL protein, SEQ ID 709.
OS Oryctolagus cuniculus.
XX
FH Key Location/Qualifiers
FT Region 24..34
FT /label= Complementarity_determining_region_1
FT Region 50..56
FT /label= Complementarity_determining_region_2
FT Region 89..100
FT /label= Complementarity_determining_region_3
XX
CC PN WO2010065072-A1.
XX
CC PD 10-JUN-2010.
XX
CC PF 24-NOV-2009; 2009WO-US006257.
XX
PR 25-NOV-2008; 2008US-0117811P.
PR 25-NOV-2008; 2008US-0117839P.
PR 25-NOV-2008; 2008US-0117861P.
PR 05-FEB-2009; 2009US-00366567.
PR 24-FEB-2009; 2009US-00391615.
PR 24-FEB-2009; 2009US-00391717.
PR 06-MAR-2009; 2009US-00399156.
PR 14-JUL-2009; 2009US-00502581.
XX
CC PA (ALDE-) ALDEN BIOPHARMACEUTICALS INC.
XX
CC PI Smith JTL;
XX
DR WPI; 2010-G61183/41.
XX
CC PT Improving survivability or quality of life of patient involves
CC PT administering to patient interleukin-6 antagonist; and monitoring patient
CC PT to assess reduction of serum C-reactive protein level or increase serum
CC PT albumin level in the patient's.
XX
CC PS Claim 33; SEQ ID NO 709; 433pp; English.
SQ Sequence 111 AA;
Qy=instant SEQ ID NO: 709
Db=SEQ ID NO: 709 of Smith et al.
Query Match 100.0%; Score 568; Length 111;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AIQMTQSPSSLSASVGDRVTITCQASQSINNELSWYQQKPGKAPKLLIYRASTLASGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AIQMTQSPSSLSASVGDRVTITCQASQSINNELSWYQQKPGKAPKLLIYRASTLASGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPDDFATYYCQQGYSLRNIDNAFGGGTKVEIKR 111
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPDDFATYYCQQGYSLRNIDNAFGGGTKVEIKR 111
Smith et al. teach that the anti-IL-6 antibody comprises a human IgG1 constant region, meeting the limitations of instant claim 28 (page 44, [0217]; pages 134-135, [0743]). Additionally, Smith et al. disclose that the Ab1 antibody comprises a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 586 and a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 588 (page 12, [0046]; pages 14-15, [0057]; page 133, Table 2, [0737, 0739]; page 338). It is noted that the amino acid sequences of SEQ ID NOs: 586 and 588 of Smith et al. are 100% identical to the human light and heavy chain constant region sequences of SEQ ID NO: 586 and 588 of the instant application, meeting the limitations of instant claim 30.
Smith et al. state that the anti-IL-6 antibody may be administered at a concentration of between about 0.1 and 20 mg/kg, such as about 0.03, 0.1, 0.3, 0.4, 0.8, and 1.0 mg/kg, meeting the limitations of instant claims 15, 16, and 20 (pages 250-251, [01235]; page 271, Example 9).
If, for example, the patient is a human and the average adult human weighs 60-85 kg, according to the dosage amounts of Smith et al., an adult human would receive a dose of 18-25.5 mg of antibody (if at a concentration of 0.3 mg/ml of antibody). Smith et al teach that the antibody may be administered with a frequency, such as, once per four weeks, meeting the limitations of instant claim 20 (page 15, [0063]). Smith et al. disclose that the anti-IL-6 antibody can be administered subcutaneously or intravenously, meeting the limitations of claim 47 (page 256, [01244-01245]; page 257, [01248]). Smith et al teach that the antibody may be administered with a frequency, such as, once per four weeks, meeting the limitations of instant claim 20 (page 15, [0063]; page 252, [01235]).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of treating cytokine release syndrome; ARDS; a symptom of ARDS associated with a coronavirus infection; or a coronavirus infection in a subject in need thereof comprising administering to the subject a composition comprising an IL-6 antibody or IL-6R antibody as taught by Shailubhai et al. by substituting Shailubhai et al.’s antibody for the anti-IL-6 antibody, dosages, and CRP detection step as taught by Smith et al. The person of ordinary skill in the art would have been motivated to make those modifications and would have expected because (i) dysregulated IL-6 signaling has been implicated in the pathogenesis of many diseases, such as COVID-19 caused by coronavirus (Shailubhai et al., page 1, [0005]) and (ii) the half-life of the Smith et al. antibody, “Ab1”, is unprecedented when compared to the half-lives of other anti-IL-6 antibodies (page 281, [01374]; Figure 21). Smith et al. also state that their Ab1 antibody has very low immunogenicity in humans and lacks glycosylation (which prevents interaction with the Fc receptor or complement) (page 281, [01374]). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
6. Claims 48, 50, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Shailubhai et al. (US 2021/0284743 or WO 2021/180821) and Smith et al. (WO 2010/065072) as applied to claims 1-3, 7, 11-13, 15, 16, 18, 20, 22, 28, 30, 47, 55, 61, 62, and 69 above, and further in view of Liu et al. (mdRxiv https://doi.org/10.1101/2020.03.01.20029769; 10 March 2020).
The teachings of Shailubhai et al. and Smith et al. are set forth above.
Shailubhai et al. and Smith et al. do not teach the subject administered a composition comprising an IL-6 antibody is receiving supplemental oxygen prior to treatment. Shailubhai et al. and Smith et al. also do not teach that the level of IL-6 and/or CRP in the subject are detected and confirmed to be greater than 20 pg/ml.
Liu et al. teach that in patients with severe COVID-19, more intensive and supportive treatment, including glucocorticoids, human immunoglobulin, interferon α, antibiotics, antiviral therapy, and oxygen therapy, was administered (page 9, “discussion”, 1st paragraph; see also pages 13-14, Table 1; Table 3). Liu et al. collect specimens from patients with COVID-19 and measure markers, such as IL-6, which may be of value in disease monitoring (abstract; pages 5-6). Liu et al. indicate that patients with severe COVID-19 have levels of IL-6 and CRP greater than 20 pg/ml, meeting the limitations of instant claim 52 (Figures 3B, 4, 5; pages 17-18). Liu et al. teach that 89.86% of the severe type COVID patients received antibiotics, 63.77% received antiviral therapy (20.29% with oseltamivir, 52.17% with arbidol and 7.25% with lopinavir/ritonavir), 42.03% received glucocorticoids, and 50.72% received human immunoglobulin (page 4; table 3; page 7). Meanwhile, 55.07% of the severe cases needed oxygen therapy, among which 27.54% received high-flow oxygen therapy, non-invasive ventilation or invasive ventilation (page 4; table 3; page 7). Liu et al. state that IL-6 level is increased significantly upon admission in severe cases as compared with nonsevere cases (Figure 1D; page 8, 2nd paragraph). Specifically, Liu et al. teach that the elevated level of IL-6 is associated with the administration of glucocorticords, human immunoglobulin, high flow oxygen inhalation, and mechanical ventilation (page 8, 2nd paragraph). Liu et al. also indicate that IL-6 decreases significantly after recovery (page 8, last paragraph; page 10, 2nd full paragraph).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of treating cytokine release syndrome; ARDS; a symptom of ARDS associated with a coronavirus infection (such as COVID-19); or a coronavirus infection (such as COVID-19) in a subject in need thereof comprising administering to the subject a composition comprising an IL-6 antibody as taught by Shailubhai et al. and Smith et al. by administration of the antibody to a subject receiving supplemental oxygen, as taught by Liu et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because (i) subjects with severe coronavirus infection (such as those receiving oxygen therapy) have significantly elevated levels of IL-6 (see Liu et al., page 4; table 3; page 7; Figure 1D; page 8, 2nd paragraph) and (ii) Liu et al. clearly state that “IL-6 is positively correlated with disease severity…and [t]argeting IL-6 may be effective in treating inflammatory cytokine storm during disease progression” (page 11, 1st full paragraph). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Conclusion
No claims are allowable.
The art made of record and not relied upon is considered pertinent to applicant's disclosure:
Channappanavar et al. Semin Immunopathol 39: 529-539, 2017 (review human coronavirus infections, cytokine storm, ARDS, and the up-regulation of IL-6) (page 531; page 532, column 1; page 534, bottom of column 1)
Chen et al. medRxiv https://doi.org/10.1101/2020.02.29.20029520; 03 March 2020 (serum SARS-Cov-2 viral load is associated with cytokine storm; IL-6 levels are significantly elevated in critically ill patients, suggesting that IL-6 should be a therapeutic target)
Chen et al. Front Med 13(5): 610-617, 2019 (teach management of CRS related to CAR-T cell therapy by anti-IL6R antibody, tocilizumab, and dexamethasone)
Rubio-Rivas et al. J Gen Internal Med 37: 1980-1987, 2022 (WHO Ordinal Scale and Inflammation Risk Categories in COVID-19. Comparative Study of the Severity Scales)
Tufan et al. Turk J Med Sci 50: 620-632, April 2020 (review of COVID-19, hyperinflammation, and immunosuppressive drugs)
*Vairy et al. (Drug Design Dev Ther 12: 3885-3898, 2018 (discuss CRS, IL-6, and IL-6R antibody, tocilizumab (page 3892, columns 12); state that a theoretical disadvantage of tocilizumab is that its administration is associated with an increase of the IL-6 level in the blood (since it binds IL-6R) and possible passive diffusion of IL-6 into the CNS, increasing the risk or neurotoxicity)
Van Rhee et al. Oncotarget 6(30): 30408-30419, 2015 (teach a phase 2 study of siltuximab (anti-IL6 Ab) in patients with multicentric Castleman disease)
Wang et al. medRxiv https://doi.org/10.1101/2020.03.06.20032342; 12 March 2020 (teach early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia)
Xu et al. ChinaXiv 05 March 2020 (teach treatment of severe COVID-19 patients with anti-IL-6R antibody, tocilizumab)
*Zhao et al. Am College Rheumatol ACR/ARHP Annual Meeting, abstract #2385, 2013
(teach anti-IL-6 Antibody Clazakizumab Is More Potent Than Tocilizumab In Blocking In Vitro and Ex Vivo IL-6-Induced Functions)
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIDGET E BUNNER whose telephone number is (571)272-0881. The examiner can normally be reached Monday-Friday 9:00 am-6:00 pm.
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BEB
Art Unit 1647
24 February 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647