DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 54-56 are cancelled. Claims 63-64 are newly added. Claims 43, 51-53, and 57-64 are pending and examined on the merits.
OBJECTIONS WITHDRAWN
Objections to Claim 62 over unmarked changes in the claim are withdrawn in view of applicant’s amendment annotating said changes.
REJECTIONS WITHDRAWN
Rejection of Claim 43 made under 35 U.S.C. 112(a) regarding new matter is withdrawn in view of Applicant’s amendment correcting the term “metastasis” to “metastases” and adding the limitation “compared to placebo”.
REJECTIONS MAINTAINED
Claim Rejections - 35 USC § 112
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 51-53 and 57-62 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
The language recited in the instant claims – “lowering the incidences of lung metastasis by five percent or greater” – does not appear anywhere in the specification, nor does any similar language. Applicant asserts that support for this amendment can be found in Table 5 (Remarks, Pg. 6, top), which is reproduced below for convenience:
PNG
media_image1.png
273
618
media_image1.png
Greyscale
The data presented in Table 5 compares the number of new lesions at different locations as a proportion of the intention-to-treat population in the study. As can be seen, the proportion of patients presenting with new lesions located in the lung were 11.8% in the durvalumab-treated cohort and 17.3% in the placebo cohort – a difference of 5.5%. However, the claims as written provide no point of comparison (i.e. compared to placebo), which would be required for one to arrive at this value given the instant disclosure.
Moreover, the claims are drawn to a decrease in “metastasis”, while Table 5 is directed to new lesions, which, as generally understood in the art, constitute metastases (metastasis is the process of tumor cells migrating or spreading from a first location to another; whereas metastases are the sites where said cells settle and establish a new growth).
Accordingly, while the disclosure provides support for lowering metastases or new lesions in the lung by five percent or greater when compared to placebo, there is no written support for lowering “metastasis” nor “five percent” in the generic.
Response to Arguments
Applicant's arguments filed 11/25/2025 have been fully considered but they are not persuasive.
Applicant argues that the instantly amended claims render the above 112(a) rejections moot. While Claim 43 was amended to recite “metastases” instead of “metastasis”, claims 51-53 and 57-61 continue to recite, or depend from claims that recite, “metastasis”, which is unsupported by the disclosure.
In addition, regarding Claims 51-53 and 57-62, the claims do not provide a point of comparison for the “five percent” difference (e.g. “compared to placebo”, as recited in amended Claim 43) and, as stated in the above rejection, the disclosure provides no support for a lowering of metastases by “five percent” in the generic.
Accordingly Claims 51-53 and 57-62 remain directed to new matter.
NEW REJECTIONS
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 63-64 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.
Claim 63 recites the limitation "administration of the first dose of durvalumab". There is insufficient antecedent basis for this limitation in the claim. Claim 63 depends from Claim 43, which does not recite “administer”, “administration”, “administered”, etc. among the method steps, does not recite a “first dose”, nor does the term “durvalumab” appear.
Similarly, Claim 64 lacks antecedent basis for the limitation "patients administered durvalumab". Claim 64 depends from Claim 43, which does not recite “administer”, “administration”, “administered”, etc. among the method steps, neither does the term “durvalumab” appear.
Claims 63 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
Newly added Claim 63 is drawn to the method of claim 43 “wherein the lowered incidence of lung metastases in the patient population is present at about 14.5 months or greater after administration of the first dose of durvalumab”. The language “wherein the lowered incidence of lung metastases in the patient population is present at about 14.5 months or greater”, or similar language, is not present in the instant specification, and Applicant’s remarks filed 11/25/2025 fail to point out where support for this new limitation can be found.
As noted in the previous office action (and reproduced above), support for fewer incidences of lung metastases/new lesions can be found in Table 5 and Figure 5 which report that the new lung lesions in the durvalumab cohort was 11.8% whereas new lung lesions in the placebo control was 17.3%. However, the specification does not disclose when these measurements were made or if this difference in new lung metastases was observable “at about 14.5 months or greater” after the first dose of durvalumab.
While ¶0154 of the specification reports that the median follow-up time within the data cutoff was 14.5 months, this is a median and encompassed a wide variety of follow up times ranging from 0.2 months through 29.9 months. Moreover, there is no disclosure within this range of when the particular population of patients presenting with new lung metastases were observed. Accordingly, newly added Claim 63 lacks written support in the application as originally filed and constitutes new matter.
Claim Rejections - 35 USC § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 43, 57-61, and 63-64 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Creelan et al. 2015 (Annals of Oncology, 26, i24.; PTO-892), herein “Creelan”, and as evidenced by DrugBank ID DB11714 (“durvalumab”; https://go.drugbank.com/drugs/DB11714; first deposited 10/20/2016; PTO-892).
Creelan teaches a method of treating stage III unresectable non-small cell lung cancer (NSCLC) in patients who have not progressed following definitive chemoradiation therapy comprising intravenous infusion of 10 mg/kg every two weeks (Q2W) of human anti-PD-L1 antibody MEDI4736 administered within 14 days after completing platinum-based chemotherapy concurrent with definitive radiation therapy (i.e. cCRT) (§ Background; § Trial Design).
Creelan teaches that this method of treating NSCLC is part of a phase 3 placebo-controlled clinical trial (NCT02125461) comprising measuring overall survival (OS) and progression free survival (PFS) as the primary endpoints.
Regarding instant claims 58-60, MEDI4736 is the same antibody as durvalumab and comprises the claimed SEQ ID NOs of Claims 58-59 as evidenced by DrugBank ID DB11714 (See VH and VL alignments below; CDRs are highlighted)
SEQ ID NO: 1 (SEQ 1); MEDI4736/durvalumab VL (DV-L)
SEQ1 1 EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DV-L 1 EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIP 60
SEQ1 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK 108
||||||||||||||||||||||||||||||||||||||||||||||||
DV-L 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK 108
SEQ ID NO: 2 (SEQ 2); MEDI4736/durvalumab VH (DV-H)
SEQ2 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DV-H 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYY 60
SEQ2 61 VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DV-H 61 VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVS 120
SEQ2 121 S 121
|
DV-H 121 S 121
Regarding independent Claims 43 and 63-64, neither the additional limitations in the preamble of Claim 43 (“lowering the incidences of lung metastases” or “increasing overall survival”), nor the particular outcomes stated in Claims 63-64 (lowered metastases at 14.5 months or increase protocol completion), confer or imply any active or structural differences to the claimed method or therapeutic, and thus performing the method of Creelan is the same as performing the instantly claimed method, regardless of the recited intended uses or outcomes inherent to its practice.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 51-53 and 57-62 are rejected under 35 U.S.C. 103 as being unpatentable over Creelan et al. 2015 (Annals of Oncology, 26, i24.; PTO-892), herein “Creelan”, as applied to claims 43, 57-61, and 63-64 above, and further in view of Antonia et al. 2016 (Annals of oncology, 27, vi421.; of record), and Rittmeyer et al. 2017 (The Lancet, 389(10066), 255-265.; of record), herein “Rittmeyer”, as evidenced by DrugBank ID DB11714 (“durvalumab”; https://go.drugbank.com/drugs/DB11714; first deposited 10/20/2016; PTO-892), NCT02008227 (ClinicalTrials.gov ID NCT02008227; Revision 2018-01-08; of record), herein “NCT02008227”, and ¶0123 of the instant specification.
The teachings of Creelan are summarized above.
Creelan does not expressly teach the active steps of “lowering the incidences of lung metastasis”, “extending progression-free survival”, or “increasing overall survival”, as recited in Claims 51-53 and/or 62. These deficiencies are cured by Antonia 2016 and Rittmeyer.
Antonia 2016 teaches results of an earlier Phase 1/2 trial (NCT01693562) for NSCLC patients treated with durvalumab (Background). Antonia teaches that patients were treated at a 10 mg/kg q2w dose (Methods). Antonia teaches that durvalumab therapy had a positive impact on ORR and overall survival (Table 1216PD).
Rittmeyer teaches the results of a trial studying the efficacy of PD-L1 antibody atezolizumab in the treatment of patients with NSCLC compared to standard of care docetaxel (Background).
Rittmeyer teaches that patients enrolled had received one to two previous platinum-based therapies for stage IIIB or IV cancer (Methods) wherein treatment had failed (see associated NCT02008227 trial details).
Rittmeyer teaches that median Overall Survival in the atezolizumab cohort was significantly longer relative to patients treated with docetaxel (15.7 months vs 10.3 months) (Findings).
Regarding Claim 62, Rittmeyer teaches that overall survival was increased compared to standard of care by more than 5% at 12 months and more than 10% at 24 months (Fig. 2).
Rittmeyer teaches that the ORR to atezolizumab is 14-18% compared to 13-16% for the standard of care (Table 2).
Rittmeyer teaches that median PFS in response to atezolizumab is 2.8 months (Table 2), compared to 4.1 months for the standard of care (Table 2).
Rittmeyer teaches that the median duration of response to atezolizumab is 16 months, compared to 6.2 months for the standard of care (Table 2).
Rittmeyer teaches that immunotherapies are commonly associated with initially lower progression-free survival or ORR compared to standard of care despite significant increases in overall survival (Pg. 264, ¶3) and duration of response (Table 2). Rittmeyer suggests that these observations may be due to delayed antitumor activity and post-progression response (Pg. 264, ¶3).
Rittmeyer teaches that treatment with the anti-PD-L1 antibody conveyed meaningful survival benefit to previously treated NSCLC patients regardless of PD-L1 expression or histology (Pg. 265, ¶1).
A method of treating NSCLC in patients who have not progressed following chemoradiation as disclosed by Creelan (10mg/kg intravenous durvalumab q2w administered within 2 weeks following cCRT) further requiring the active steps of “lowering the incidences of lung metastasis”, “extending progression-free survival”, and “increasing overall survival” as recited in Claims 51 and/or 62 would have been obvious to one of ordinary skill in the art.
The skilled artisan would have been motivated to include these additional steps because both OS and PFS were stated outcome measures for the NCT02125461 study taught by Creelan. There would have been a reasonable expectation of success based on the previously reported benefit of durvalumab on overall response and overall survival taught by Antonia 2016, and the treatment of NSCLC with PD-L1 antibody atezolizumab wherein overall survival was improved relative to standard of care by more than 10% and PFS was improved for at least a subset of patients.
Regarding the specific limitations of Claims 52-53, Rittmeyer teaches a lower PFS than required by instant claims. Importantly, however, unlike the PACIFIC trial of NCT02125461 wherein the patient population that had not yet progressed after chemoradiation therapy and the control group was administered placebo, the OAK study of Rittmeyer enrolled patients with active disease and the anti-PD-L1 cohort was compared with standard of care chemotherapy – not placebo.
It would have been obvious to one of ordinary skill in the art that a greater lead time (i.e. a patient that had not yet progressed after therapy/stable disease) would obviate the delayed response associated with immunotherapy taught by Rittmeyer and, accordingly, the skilled artisan would expect a greater benefit to progression free survival in a patient population with currently stable disease according to the method of treatment of the combined teachings of Creelan, Rittmeyer, and Antonia 2016. There would have been a reasonable expectation of success because Creelan teaches the patient population has not progressed following first line therapy, Antonia 2016 teaches promising responses in patients treated with durvalumab during the NCT02125461 (PACIFIC) trial, and Rittmeyer teaches that despite initially lower progression-free survival to standard of care, response to anti-PD-L1 therapy is significantly more durable.
Additionally, regarding the limitation “lowering the incidences of lung metastases by 5 percent or greater”, such an outcome would necessarily be linked to progression free survival endpoint assessments discussed above because new lung metastases by their very nature constitute a “progression” of the disease – and thus an increased progression free survival inherently comprises a lowering of number of new lesions/metastases.
Moreover, the claims provide no timeframe in which this “five percent” reduction is achieved. Therefore, given the progressive nature of cancer, it would be obvious to one of ordinary skill in the art that incidences of new metastases in an untreated population would outpace those receiving treatment by at least five percent at some point – particularly if there is an expectation that said treatment is effective as discussed above.
Finally, regarding the specific outcomes/results recited in Claims 52-55 and 63-64, because the combined method of Creelan, Antonia 2016, and Rittmeyer comprises all the same active steps as the methods of the instant claims, including the same drug (durvalumab) administered at the same dose (10mg/kg) and the same frequency (q2w) to the same patient population as instantly claimed, the method would have inherently been capable of producing the same outcomes.
Response to Arguments
Applicant's arguments filed 11/25/2025 have been fully considered but they are not persuasive because:
First, Applicant argues that the new limitation of the amended claims, wherein the antibody is administered “within 42 days”, is not taught by the previously applied references. In response, the primary reference was updated. As stated above, the updated reference Creelan, which teaches the same NCT02125461 trial as the previously relied upon referece, teaches that the anti-PD-L1 antibody is administered within 14 days after completing cCRT, which satisfies the newly added limitation of “within 42 days”.
Applicant further argues two unexpected results associated with the claimed method – First: that durvalumab was effective regardless of PD-L1 status; and Second: that because sequential administration of a PD-L1 antibody was previously reported to have been inferior to simultaneous administration, that the reported outcomes would have been “surprising and unexpected”.
Regarding these purportedly unexpected results, it is pointed out that Rittmeyer (summarized above) teaches a method of treating NSCLC patients with human anti-PD-L1 antibody atezolizumab after prior therapy (i.e. “sequential”), including those having received combined chemoradiation (see NCT02008227 inclusion criteria). Moreover, Rittmeyer teaches that this sequential treatment with an anti-PD-L1 antibody was effective “regardless of PD-L1 expression or histology”. Accordingly, in view of the state of the art prior to the instantly filed application, one of ordinary skill in the art would not have found it particularly unexpected or surprising that sequential administration of an anti-PD-L1 antibody to an NSCLC patient following chemoradiation therapy would be effective – regardless of whether PD-L1 expression is detected.
While the referenced studies had not reported long-term outcomes before the instant filing date, the additional treatment results required by the instant claims were each stated outcome measures in the NCT02125461 (“PACIFIC”) trial. Moreover, the preliminary data from earlier dose-escalation studies with durvalumab – as well as contemporary trials employing different PD-L1 antibodies in treating NSCLC – provide the skilled artisan with a reasonable expectation of success in achieving the claimed outcomes by performing the method taught by Creelan.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRYAN WILLIAM HECK whose telephone number is (703)756-4701. The examiner can normally be reached Mon-Fri 8:00am - 5:30pm.
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, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643