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. Applicant's amendment, filed on 04/17/2025, is acknowledged.
3. Claims 1-3, 5, 7, 9-16, 19-20 and 22-26 are pending and being acted upon presently.
4. Applicant’s IDS, filed 11/19/2025, is acknowledged.
5. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], 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.
6. Claim 20 is rejected under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), 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 20 depends from claim 19 which recites “administering a recurring effective dose of 200 mg or less per month of tocilizumab” however, claim 20 recites “administered once every 1-8 weeks” which does not further limit the monthly administration of claim 20. 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.
7. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
8. Claims 20 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
(i) The recitation “administered once every 1-8 weeks” in claim 20 is ambiguous. Claim 20 depends from claim 19 which recites “administering a recurring effective dose of 200 mg or less per month of tocilizumab”, it is not clear how the monthly administration is now weekly administration.
9. 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.
10. Claims 1-3, 5, 7, 9-16, 19-20 and 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over Odièvre et al (Am J Hematol . 2020 May 16;95(8):E192–E194, IDS) in view of US 20230192872 A1 /WO 2021202919 A1.
Odièvre et al teach that dramatic improvement after tocilizumab of severe COVID‐19 in a child with sickle cell disease and acute chest syndrome. Odièvre et al teach that a recently reported a favorable outcome of an acute chest syndrome (ACS) related to a SARS‐Cov‐2 infection treated with tocilizumab (TCZ), in a 45‐year‐old male patient with homozygous sickle cell disease (SCD). Following this successful observation, TCZ was administered to a teenage girl with SCD who developed a severe COVID‐19 associating ACS and pulmonary embolism. This 16‐year‐old girl has a severe form of homozygous SCD with bilateral ischemic retinopathy.
Given the recurrence of vaso‐occlusive crises and abnormal transcranial doppler evaluations, she was treated with exchange transfusions from 5 to 11 years old, switched thereafter for hydroxyurea (22 mg/kg/day), with a favorable clinical outcome on vaso‐occlusive events. She had no history of ACS or pulmonary hypertension, and her respiratory function and chest radiography were previously normal. She was confined to her home with her parents. One week after her parents developed COVID‐19 symptoms (cough, fever and anosmia), she presented with an isolated fever treated by acetaminophen. Seven days later, she developed an ACS characterized by an acute chest pain associated with a respiratory distress syndrome. Real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) of nasopharyngeal swabs confirmed the SARS‐Cov‐2 infection. Levels of C‐reactive protein (355 mg/L), LDH (446 U/L) and D‐dimer (23 611 ng/mL) were increased. Given the tachycardia and elevation of D‐dimer in a SCD patient with COVID‐19, a pulmonary embolism was suspected, which is assumed to be more frequent in this context. Indeed, the computed tomography pulmonary angiography (CTPA) showed a bilateral pulmonary embolism complicating the ACS, and was compatible with COVID‐19 (bilateral consolidations with a halo sign on the right side, Figure S1). The patient was admitted to an intensive care unit (ICU) and required non‐invasive ventilation, red blood cell exchange transfusion followed by simple transfusion (hemoglobin nadir 6.4 g/dL), and anticoagulation (i.e., one or more additional therapeutics). Because of the severity of the disease, and based on the experience of COVID‐19 in SCD adult patients, she also received one pulse of intravenous tocilizumab (TCZ, 8 mg/kg). Plasma level of Interleukin (IL)‐6 was extremely high (629 pg/mL; normal <8.5 pg/mL) and was even higher after TCZ (724 pg/mL), in line with IL‐6 receptor blockade (testing after TCZ treatment). The patient improved rapidly after TCZ treatment. Non‐invasive ventilation was stopped 4 days after TCZ, with no oxygen requirement thereafter, allowing the discharge from ICU. She was then referred to a medical unit where CTPA was repeated 5 days after TCZ. A dramatic improvement occurred with a disappearance on the right, and a decrease on the left of both the pulmonary embolism and the consolidation opacities, as previously described by Cellina et al. (Figure S1). She was finally discharged from the hospital 11 days after admission, with an oral anticoagulant treatment to be continued for a total of 6 weeks.
A single injection of the treatment was followed by a rapid improvement of the patient's respiratory status, together with a dramatic improvement of CTPA images. A second and a third dose of TCZ can be administered after 12 and 24‐36 hours respectively. A favorable CT evolution has been previously described in an adult patient 7 days after two TCZ injections at 12 hour intervals. Cytopenia and increased transaminases have been reported and need to be monitored. No adverse effect of TCZ was observed in our patient. TCZ seems to be safe and effective in adults as well as in children, in association with the usual treatment of severe ACS, including non‐invasive ventilation and blood exchange transfusion (see entire document).
The reference teachings differ from the claimed invention only in the recitation that of an effective dose of 200/100/50 mg or less of TCZ in claims 1, 3, 5, 19, 22 and 23; subcutaneously in claim 9; daily/weekly/monthly in claims 5, 7, 10.
The teachings of the US `872 and the `919 publication are identical, the teachings of the `872 is used in the rejection.
The `872 publication provides pharmaceutical compositions comprising doses of 200 mg or less of tocilizumab and methods for the treatment of SARS-CoV-2 infections, COVID-19, inflammation secondary to such infections, and symptoms or other conditions arising as a result thereof. A method of treating a subject infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) comprising administering an effective dose of 200 mg or less of tocilizumab to the subject, wherein the effective dose comprises less than 100 mg of tocilizumab, wherein the effective dose comprises less than 50 mg of tocilizumab, wherein the subject is administered multiple doses comprising less than 400 mg total of tocilizumab, wherein the multiple doses total less than 200 mg of tocilizumab, wherein tocilizumab is administered once daily, wherein tocilizumab is administered once every 2-3 days, wherein tocilizumab is administered subcutaneously, wherein tocilizumab is administered intravenously, wherein the tocilizumab is co-administered with one or more additional therapeutics. A method comprising: (a) testing a subject or a biological sample from a subject to determine the appropriateness of tocilizumab administration to treat/prevent cytokine release syndrome as a result of COVID-19; (b) administering a dose of tocilizumab, wherein testing comprises determining the subject's C-reactive protein level, wherein testing comprises determining the subject's serum IL-6 level, further comprising: (c) testing a subject or a biological sample from a subject to determine the effectiveness of the tocilizumab administration, further comprising: (d) determining a treatment course of action based on the testing of step (a) and/or step (c) (see published claims). The `872 publication also teach that Tocilizumab is typically administered (e.g., for treatment of adults with moderate-to severe active rheumatoid arthritis (RA)) via intravenous (IV) infusion or subcutaneous injection (page 17, lines 23+). Tocilizumab is provided in 10-200 mg doses (see page 18, lines 33+). Methods are provided for the treatment or prevention of viral
infection by the co-administration of tocilizumab with one or more additional therapeutics or
therapies (e.g., for the treatment of viral infection (e.g., SARS-CoV-2), for treatment of
20 COVID-19, for treatment/prevention of CRS, etc.) (page 20, lines 17+). The `872 publication provides provided herein are methods comprising: (a) testing a subject or a biological sample from a subject to determine the appropriateness of tocilizumab administration to treat/prevent cytokine release syndrome as a result of COVID-19; (b) administering a dose of tocilizumab consistent with the methods herein. Testing comprises determining the subject's C-reactive protein level, interleukin-6 level, RT-qPCR testing to determine SARS-CoV-2 infection, chest x-ray, metabolite testing, or any other assays or biomarkers described herein. Methods further comprise (c) testing a subject or a biological sample from a subject to determine the effectiveness of the tocilizumab administration. Methods further comprise ( d) determining a treatment course of action based on the testing of step (a) and/or step (c) (page 4, lines 4+). Example 1 directed to clinical study of low-dose tocilizumab administration to hospitalized, nonmechanically ventilated adult patients with COVID-19 pneumonitis. A dose range from 40 to 200 mg was evaluated, with allowance for one 25 repeat dose at 24 to 48 hours. Example 2 is directed to clinical trial comparing low doses of tocilizumab with standard of care only.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the dosages taught by the `872 publication in the treatment of severe COVID‐19 in adults as well as in children with sickle cell disease and acute chest syndrome taught by Odièvre et al because the those dosage are effective amount in the treatment of SARS-CoV-2 infections, COVID-19, inflammation secondary to such infections, and symptoms or other conditions arising as a result thereof. The skilled in the art, based upon knowledge of compounds having similar physiological or biological activity, would be able to discern an appropriate dosage or method of use.
"[W]here there is a range disclosed in the prior art, and the claimed invention falls within that range, the burden of production falls upon the patentee to come forward with evidence" of teaching away, unexpected results, or other pertinent evidence of nonobviousness. Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013).
The Board stated that "all that remained to be achieved over the prior art was the determination that a specific dose within a previously suggested dose range, and its corresponding dosing schedule, would have been safe and effective for the treatment of human patients." Genzyme Therapeutic Prods. v. Biomarin Pharms., No. 2015-1720.
When other methods similar to a claimed method have been successful such as taught by the `872 publication, the court has determined there would have been a reasonable expectation of success. For example, in Velander v. Garner, 348 F.3d 1359, 1379 (Fed. Cir. 2003), a reasonable expectation of success was found for a method of producing a particular protein when several other proteins had been produced in a similar way.
The court has also determined that the availability of specific instructions to achieve the claimed subject matter can form the basis for a reasonable expectation of success. In Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1367-68 (Fed. Cir. 2007), a reasonable expectation of success was found where the prior art included several references with directions for narrowing the possible salts previously approved and the result could be verified by routine trial-and-error procedures.
The `872 publication indicate the same dose regimen of TCZ at 200 mg or less intravenous (IV) had previously been considered, and used, with TCZ therapies, those of primary skill in the art would have had a reasonable expectation of success in using the claimed TCZ regimen as claimed.
The `872 publication demonstrates that a dosing of 200mg or less of TCZ is criteria in the treatment of SARS-CoV-2 infections, COVID-19, inflammation secondary to such infections, and symptoms or other conditions arising as a result thereof known in the art, it is known that these criteria had been met for TCZ antibody. Those skilled in the art would have had a reasonable expectation that the claimed treatment regimen of the TCZ would have been successful.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
11. No claim is allowed.
12. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
(a) WO 2022/096547
The `547 publication is directed to methods of treating an acute chest syndrome in a patient suffering from sickle cell disease comprising administering to the patient a therapeutically effective amount of an IL-6 inhibitor, wherein the anti-IL-6R inhibitors is an antibody that binds to the amino acid sequence that ranges from the amino acid residue at position 20 to the amino acid residue 365 in SEQ ID NO:2, wherein the anti-IL-6R antibody is tocilizumab, sarilumab, or levilimab (BCD-089), wherein the anti-IL-6R antibody is tocilizumab (see published claims).
(b) Kolb et al. Effective Use of Tociluzimab, an Anti-Interleukin 6 Agent for the Treatment of Steroid-Refractory Grade IV Intestinal Acute Graft-Versus-Host Disease in a Child with Sickle Cell Disease. Abstracts / Biol Blood Marrow Transplant 20 (2014) S297-S315, Abs # 482.
Kolb et al teach that an appropriate dose and schedule has not been established for SR aGVHD with a history of sickle cell disease. Due to the severity of this child’s disease and demonstrated lack of response to conventional therapies, we utilized TCZ as a salvage therapy and found it to be well tolerated and potentially life saving.
(c) Lee et al. Targeting Macrophage Activation in Hyperhemolysis Syndrome with Novel Use of Tocilizumab. Blood (2018) 132 (Suppl_1) : 4933.
Lee et al reported the successful use of tocilizumab supported with HBOC-201 in a sickle cell disease (SCD) patient with life-threatening acute HHS refractory to standard IVIG and steroid therapy who experienced a Hb nadir of 2.1 g/dL (abstract).
(d) Geiszler et al. Hyperhemolysis Syndrome Complicated by Acute Pulmonary Hypertension and Right Ventricular Failure in a Patient with Sickle Cell Disease. American Journal of Respiratory and Critical Care Medicine, Volume 203, Issue Supplement_1, May 2021, Page A3302.
Geiszler et al present a case of delayed HS complicated by acute right ventricular failure and cardiogenic shock after RBC transfusion to treat an acute pain crisis. Case: A 24-year-old male with SCD requiring recent RBC transfusion for acute pain crisis presented with substernal chest pain. He was hemodynamicaly stable, and a plain chest radiograph (CXR) was clear. He received two doses of tocilizumab in an attempt to treat HS.
(e ) De Melo et al. Tocilizumab for the Treatment of Severe COVID-19 Acute Chest Syndrome in a Pediatric Patient with Sickle Cell Disease. American Journal of Respiratory and Critical Care Medicine, Volume 203, Issue Supplement_1, May 2021, Page A3294.
De Melo et al describe the case of a pediatric SCD patient with COVID-19 and ACS who was successfully treated with an anti-IL-6 receptor monoclonal antibody (tocilizumab). Description: A 7 year-old female with homozygous SCD presented with a vaso-occlusive crisis characterized by right arm pain that progressed to fever and chest pain. A diagnosis of ACS was made based on chest pain, tachypnea, fever, and a right middle lobe infiltrate on chest x-ray. The patient’s mother and father were previously diagnosed with COVID-19. Real‐time reverse transcription‐polymerase chain reaction (RT-PCR) was positive for SARS-CoV-2. The c-reactive protein (6.2 mg/dL) and ferritin (165.3 ng/mL) were elevated while the patient had a profound lymphocytopenia (740 cels/µL). The patient developed respiratory failure requiring invasive mechanical ventilation and transfer to the intensive care unit within 24 hours. Baseline serum IL-6 level was elevated to at 14.2 pg/mL (normal ≤ 2 pg/mL). Given the patient’s rapid clinical deterioration and evidence of hyperinflammation, tocilizumab was started on the second day of admission at 8 mg/kg with a repeat dose 24 hours later. The patient also received broad antimicrobial coverage, methylprednisolone, remdesivir and exchange transfusion. She required chest tube placement for a right-sided pleural effusion. The serum IL-6 level significantly increased to 256.5 pg/mL after the second dose of tocilizumab, a finding that has been reported with IL-6 receptor blockade. Fever and inflammatory markers improved rapidly after tocilizumab treatment (Table 1). The patient was extubated 15 days after the final dose of tocilizumab and discharged after 37 days. Discussion: IL-6 is a pro-inflammatory cytokine that is elevated during vaso-occlusive crises and upregulated during SARS-CoV-2 infections. tocilizumab is a monoclonal antibody against the IL-6 receptor. In our pediatric patient, the use of tocilizumab was a safe and effective adjunctive therapy for the management of severe COVID-19 ACS. Randomized controled trials are needed to further study the safety and efficacy of tocilizumab in this patient population.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 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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June 30, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1641
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