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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/27/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 8/5/2024 is acknowledged.
Claim 36-43 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II-VII there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/5/2024.
Status of Claims
Cancelled: 1-23
Withdrawn: 36-43
Examined Herein: 24-35
Priority
Acknowledgment is made of applicant's claim for priority under based upon an application filed in EP 19382195.6 on 3/19/2019 and PCT/EP2020/057585 on 3/19/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Rejections
The rejection of claims 24, 25, 29-31, 33, and 35 under 35 U.S.C. 103 over Soucek is hereby withdrawn in view of Applicant’s substantive amendment to claim 24.
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 24-27 and 29-35 are rejected under 35 U.S.C. 103 as being unpatentable over Tweedle (US 2020/0254116 A1, Filed 8/20/2018), in view of Soucek (US 2016/0122415 A1, Published 5/5/2016).
With respect to claim 24, Tweedle discloses a method for detecting cancer cells (including lung cancer cells) in a subject comprising:
Administering by a pulmonary route (intranasal or inhalant) a conjugate comprising a polypeptide that targets cancer cells and a detectable label;
Waiting a sufficient time (30 minutes to 48 hours) to allow for the conjugate to enter the cancer cells;
Detecting the cancer cells by applying an imaging technique (e.g., MRI, SPECT, PET, optical imaging, etc.) to detect the site of accumulation of the conjugate in the cancer cells of the subject;
Wherein the detection of the site of accumulation is carried out at least 24 hours (up to 48 hours) after the administration of the conjugate. [Tweedle, 0011, 0136, 0174, 0177-0180, 0187, 0213, 0221, 0235-0237]
With respect to claim 25, Tweedle discloses a diagnostic method for the detection of a lung tumor in a subject comprising:
Administering by a pulmonary route (intranasal or inhalant) a conjugate comprising a polypeptide that targets cancer cells and a detectable label;
Waiting a sufficient time (30 minutes to 48 hours) to allow for the conjugate to enter the cancer cells;
Detecting the cancer cells by applying suitable detection means (e.g., MRI, SPECT, PET, optical imaging, etc.) to detect the site of accumulation of the conjugate in the cancer cells of the subject;
Wherein the detection of the site of accumulation is carried out at least 24 hours (up to 48 hours) after the administration of the conjugate.
Identifying a lung tumor if a specific label is detected. [Tweedle, 0011, 0136, 0174, 0177-0180, 0187, 0213, 0221, 0235-0237]
With respect to claim 27, Tweedle discloses that the detectable label may be 18F, 47Sc, 62Cu, 64Cu, 67Ga, 68Ga, 86Y, 89Zr, 99mTc, 105Rh, 123I, 124I, 153Sm, 159Gd, 161Tb, 166Dy, 166Ho, 186Re, 198Au, 199Au, 212Bi, and 225Ac. [Tweedle, 0138, 0177, 0202-0204]
With respect to claim 29, Tweedle discloses that the lung tumor may be a primary tumor from small cell lung cancer or non-small cell lung cancer. [Tweedle, 0174, 0236, 0237]
With respect to claim 30, Tweedle discloses that the lung tumor may be an adenocarcinoma. [Tweedle, 0236]
With respect to claim 32, Tweedle discloses that the detection of the site of accumulation of the conjugate is carried out between 30 minutes and 48 hours after the administration of the conjugate. [Tweedle, 0179]
With respect to claim 33, Tweedle discloses the conjugate may be administered by oral inhalation or by intranasal administration. [Tweedle, 0213, 0221]
With respect to claim 34, Tweedle discloses that the dose of the conjugate will necessarily vary depending on factors specific to the patient and may also depend on the body site under examination, method of administration, type of label used, and the like. The determination of specific procedures is, however, routine to the skilled artisan. [Tweedle, 0181, 0227]
With respect to claim 35, Tweedle discloses that the conjugate may be administered at least one more time. [Tweedle, 0227]
Moreover, Tweedle discloses that the method is not limited to the disclosed HN17 and/or HN18 peptide. Rather, a peptide that targets a tumor cell or other cancer-specific protein may be used. [Tweedle, 0008, 0009, 0129, 0173]
Tweedle does not disclose that the conjugate comprises a polypeptide comprising the sequence of SEQ ID NO: 1 or a functionally equivalent variant thereof.
However, with respect to claims 24 and 25, Soucek discloses a method for treating lung cancer cells in a subject comprising:
Administering by a pulmonary route (intranasal) a polypeptide comprising the sequence of SEQ ID NO:1 or a functionally equivalent variant thereof and a detectable label (a fluorophore);
Waiting a sufficient time to allow for the polypeptide to enter the cancer cells;
Soucek further discloses that the site of accumulation of the polypeptide may be detected by conjugating the polypeptide with a detectable label and applying an imaging technique; [Soucek, 0191] The polypeptide may be conjugated with radioisotopes. [Soucek, 0118, 0121-0127, 0132]
With respect to claim 26, Soucek implicitly discloses that the functionally equivalent variant of SEQ ID NO: 1 is selected from the group of SEQ ID NO: 4 – 10. Specifically, Soucek discloses that a functionally equivalent variant of Omomyc may be administered instead of Omomyc. [Soucek, 0043, 0082] Soucek defines a functionally equivalent variant as any polypeptide which results from the deletion, insertion, or addition of one or more amino acids with respect to the polypeptide Omomyc. [Soucek, 0051] Instant SEQ ID NO: 4 differs from SEQ ID NO: 1 in that it contains an additional methionine (M) at the N-terminus. Instant SEQ ID NO: 5 differs from SEQ ID NO: 1 in that the final cysteine is replaced with X, wherein X is any amino acid other than cysteine. Instant SEQ ID NO: 6 differs from SEQ ID NO: 1 in that it contains an addition methionine (M) at the N-terminal and in that the final cysteine is replaced with X, wherein X is any amino acid other than cysteine. Instant SEQ ID NO: 7 differs from SEQ ID NO: 1 in that the final cysteine is replaced with serine. This modification is considered an amino acid substitution. Instant SEQ ID NO: 8 differs from SEQ ID NO: 1 in that the final cysteine is replaced with serine and in that it contains an additional methionine (M) at the N-terminus. Instant SEQ ID NO: 9 differs from SEQ ID NO: 1 in that the final cysteine is replaced with alanine. Instant SEQ ID NO: 10 differs from SEQ ID NO: 1 in that the final cysteine is replaced with alanine and in that it contains an additional methionine (M) at the N-terminus. Thus, instant SEQ ID NO: 4-10 involve modifications to Omomyc, including amino acid additions and substitutions, and as functionally equivalent variants of Omomyc and may be administered instead of Omomyc.
With respect to claim 29-31, Soucek discloses that the lung tumor is KRas-GD12. [Soucek, 0192] KRAS is a mutant lung adenocarcinoma. Lung adenocarcinoma is a subtype of non-small cell lung cancer.
With respect to claim 33, Soucek discloses that administration by pulmonary route is carried out by intranasal instillation. [Soucek, 0191, 0192]
With respect to claim 34, Soucek discloses that the dose of Omomyc administered may range from 0.01 mg/kg to 500 mg/kg. Soucek additionally discloses that the appropriate dosage of Omomyc will depend on different factors such as the type of cancer to be treated, the severity and course of the disease, whether the composition is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the polypeptide, and the discretion of the attending physician. [Soucek, 0080, 0142]
With respect to claim 35, Soucek discloses that Omomyc may be administered at least one more time to monitor the progression of the lung tumor or the effect of a therapy. [Soucek, 0081, 0142, 0193]
Moreover, Soucek discloses that Omomyc can translocate to the nucleus of target tumor cells and localize (or accumulate) in the lungs. [Soucek, 0072, 0191]
Modifying the conjugate in the method disclosed by Tweedle by selecting Omomyc or a functionally equivalent variant thereof as the targeting polypeptide results in the method of claim 24, 25, and 26.
Further modifying the method disclosed by Tweedle and Soucek by selecting a subject having KRAS-mutant adenocarcinoma results in the method of claim 29-31.
Further modifying the method disclosed by Tweedle and Soucek so that the administered dose of the conjugate ranges from 0.01 mg/kg to 500 mg/kg results in the method of claim 34.
It would be obvious to one of ordinary skill in the art to modify the conjugate administered in the method disclosed by Tweedle by selecting Omomyc or a functionally equivalent variant thereof as the targeting polypeptide and have a reasonable expectation of success. Tweedle discloses a method for detecting cancer cells (e.g., lung cancer cells) in a subject comprising administering a conjugate comprising a polypeptide that targets cancer cells and a detectable label (e.g., a radioisotope). Soucek discloses that Omomyc is a peptide that targets lung cancer cells. Moreover, Soucek discloses that Omomyc may be conjugated to a detectable label (fluorophore or radioisotope) and administered to a subject in need thereof. Accordingly, the combined teachings of Tweedle and Soucek reasonably suggest that Omomyc may function as the polypeptide that targets cancer cells in the method disclosed by Tweedle. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Soucek discloses that Omomyc can translocate to the nucleus of target tumor cells and localize (or accumulate) in the lungs. [Soucek, 0072, 0191] Therefore, one would have been motivated by the expectation that selecting Omomyc or a functionally equivalent variant thereof as the targeting polypeptide would enable the conjugate to translocate and localize in the cancer cells of the subject when administered.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Tweedle and Soucek by selecting a subject having KRAS-mutant adenocarcinoma and have a reasonable expectation of success. Tweedle and Soucek disclose a method for detecting cancer cells in a subject comprising administering a conjugate comprising Omomyc and a detectable label. Tweedle discloses that the cancer cells may be from lung cancers such as small cell lung cancer and non-small cell lung cancer. Soucek discloses that Omomyc is preferably administered to a subject having KRAS-mutant adenocarcinoma. Moreover, KRAS-mutant adenocarcinoma is a subtype of non-small cell lung cancer. Accordingly, the combined teachings of Tweedle and Soucek reasonably suggest that Omomyc may be administered to a subject having KRAS-mutant adenocarcinoma. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Soucek discloses that Omomyc reduces tumor burden in a subject having KRAS-driven lung adenocarcinoma. Therefore, one would have been motivated by the expectation that selecting a subject with KRAS-mutant adenocarcinoma would enable the conjugate to translocate to and localize in the subject’s cancer cells and reduce tumor burden when administered, thereby enabling the method to have a theragnostic effect.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Tweedle and Soucek so that the administered dose of the conjugate ranges from 0.01 mg/kg to 500 mg/kg and have a reasonable expectation of success. Tweedle and Soucek disclose a method for detecting cancer cells in a subject comprising administering a conjugate comprising Omomyc and a detectable label. Soucek discloses that the dose of Omomyc administered may range from 0.01 mg/kg to 500 mg/kg. Accordingly, the combined teachings of Tweedle and Soucek suggest that the dose of the conjugate administered may range from 0.01 mg/kg to 500 mg/kg. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Soucek discloses that an appropriate dosage level of Omomyc is generally about 0.01 to 500 mg/kg patient body weight per day, which can be administered in single or multiple doses. [Soucek, 0081, 0142] Therefore, one would have been motivated by the expectation that administering the conjugate at a dose from 0.01 mg/kg to 500 mg/kg would be appropriate for the subject.
Claims 24-35 are rejected under 35 U.S.C. 103 as being unpatentable over Tweedle and Soucek, as applied to claims 24-27 and 29-35 above, and further in view of Yang (CN 202982303 U, Published 6/12/2023).
With respect to claim 25, Tweedle and Soucek disclose the teachings above.
Tweedle further discloses that the subject may be an animal, such as a nude mouse harboring a tumor or cancerous tissue. [Tweedle, 0123] Moreover, Tweedle discloses that the imaging technique may include, for example, PET or SPECT. [Tweedle, 0139, 0179] However, major conventional imaging modalities such as PET/CT have very limited application intraoperatively due to their large size and slow image collection times. [Tweedle, 0244]
Tweedle and Soucek do not disclose that the imaging technique is mPET/CT imaging.
However, with respect to claim 28, Yang discloses that mPET/CT allows for the functional and anatomical imaging of small rodents, including mice, in vivo and on the distribution of drugs in the bodies of small animals. Yang further discloses that mPET/CT can obtain physiological and pathological data about animals, including drug distribution and interactions, which supports tumor research. mPET/CT is superior to other imaging techniques because it provides kinetic data on the order of seconds, allows for rapid imaging of physiological and pharmacological processes in vivo, and is relatively non-invasive. [Yang, 0002]
Modifying the method disclosed by Tweedle and Soucek by selecting mPET/CT as the imaging technique results in the method of claim 28.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Tweedle and Soucek by selecting mPET/CT as the imaging technique and have a reasonable expectation of success. Tweedle and Soucek disclose a method for detecting lung cancer cells in a subject comprising applying an imaging technique such as PET to a subject (i.e., mice harboring a tumor or cancerous tissue). Yang discloses that mPET/CT enables functional and anatomical imaging of small rodents, including mice, to obtain physiological and pathological data. Accordingly, the combined teachings of Tweedle, Soucek, and Yang reasonably suggest that the step of applying an imaging technique to a mouse in the method disclosed by Tweedle and Soucek may be carried out using mPET/CT. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the instant case, Tweedle discloses that major conventional imaging modalities such as PET/CT have very limited application intraoperatively due to their large size and slow image collection times. [Tweedle, 0244] However, Yang discloses that mPET/CT provides kinetic data on the order of seconds, allows for rapid imaging of physiological and pharmacological processes in vivo, and is relatively non-invasive, particularly in small animals like mice. [Yang, 0002] Therefore, one of ordinary skill in the art would be motivated by the expectation that selecting mPET/CT as the imaging technique would allow for rapid imaging of physiological and pharmacological processes in small animals to be carried out in the method disclosed by Tweedle and Soucek, thereby overcoming the drawback of PET/CT expressed by Tweedle.
Response to Arguments
Applicant's arguments filed 2/27/2026 have been fully considered but they are not persuasive.
Applicant asserts, “It is well-settled that an obviousness rejection requires at least a showing that all of the claim elements are met by the combined teachings of the prior art. In the present case, amended claim 24 recites that the detection of the site of accumulation of the conjugate is carried out at least 24 hours after the administration of the conjugate to a subject in need thereof, which is not disclosed in Soucek. In contrast, Soucek only provides fluorescent imaging at 10 minutes after intranasal administration (paragraph [0191] and Figs. 1 0A-1 OB) to show that a fluorophore-labeled Omomyc reaches lung at that time point, and does not disclose any detection or imaging at or after 24 hours after
administration” [Remarks 2/27/2026, Page 7] and “As discussed above, Soucek does not teach all elements of instant claim 24. Tweedle does not cure the deficiencies of Soucek. Additionally, the instantly claimed invention is based on surprising findings as discussed above.” [Remarks 2/27/2026, Page 8]
Applicant’s arguments are not persuasive because the combination of Tweedle and Soucek does show all of the claim elements. Tweedle discloses that the detection of the site of accumulation occurs at least 24 hours, specifically up to 48 hours, after the conjugate is administered. Accordingly, the deficiency of Soucek purported by Applicant is cured by Tweedle.
Applicant asserts, “Applicant respectfully submits that this advantageous property-tumor accumulation accompanied by wash-off from healthy lung tissue by 24 hours -establishes a time-dependent differential biodistribution that is unexpected to one skilled in the art. Soucek is silent regarding any later-time biodistribution… Thus, the tumor-localized accumulation observed at approximately 24 hours in the instant application is not predictable in view of Soucek. [Remarks 2/27/2026, Page 7-8]
Applicant arguments are not persuasive because allegations of results must be commensurate in scope with the claimed invention and, in fact, unexpected and unobvious. MPEP 716.02 & MPEP 716.02(d). However, the results provided by the Applicant are neither.
Applicant’s alleges that the claimed conjugate possesses the advantageous property of tumor accumulation accompanied by wash-off from healthy lung tissue by 24 hours. This result is based on the specific conjugate, Omomyc-DFO-89Zr. However, claim 24 recites a conjugate comprising Omomyc and a (generic) detectable label. The specification defines a detectable label as any biocompatible compound with the capacity to be detected either directly or indirectly, the use of which facilitates the differentiation of different parts of the image, by increasing the “contrast” between those different regions of the image. [Specification, 0127] Detectable labels may include, but are not limited to, radioactive substances (e.g., radioisotopes, radionuclides, radiolabels or radiotracers), dyes, contrast agents, fluorescent compounds or molecules, bioluminescent compounds or molecules, enzymes and enhancing agents (e.g., paramagnetic ions). [Specification, 0128] Accordingly, 89Zr cannot reasonably be considered representative of the entire genus of detectable labels. Thus, the advantageous property purported by Applicant cannot reasonably be attributed to the broad conjugate of claim 24. The showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. Applicant has provided no evidence that a conjugate comprising any species that falls within the described genus of detectable labels can achieve the same effect achieved by Omomyc-DFO-89Zr.
Moreover, the purported advantageous property achieved by Omomyc-DFO-89Zr is not unexpected since the conjugate comprises 89Zr. 89Zr is known in the art to remain in cancerous tissue for a prolonged period.
Cornelis discloses that after 89Zr diagnostic scans are obtained and interpreted, avid lesions retain activity for several additional days. [Cornelis, Page 399, Col. 1, Paragraph 1] Cornelis discloses a method for detecting cancer cells comprising administering 89Zr-labeled radiotracers to subjects with metastatic prostate or breast carcinoma. [Cornelis, Abstract] The 89Zr-peptide conjugates remained detectable at the tumor sites for up to seven days after administration. [Cornelis, Figure 1, 2, 3]
This effect can reasonably be attributed to 89Zr alone, rather than the conjugated peptide because 89Zr retains activity in vivo even when not conjugated to a peptide. Abou discloses a method comprising administering [89Zr]Zr-chloride, [89Zr]Zr-oxalate, or [89Zr]Zr-phosphate to mice. [Abou, Abstract] 89Zr remained detectable at 24 hours after administration. [Abou, Page 14, Figure 5]
Moreover, this effect is not unique to 89Zr alone. Other radioisotopes also remain in cancerous tissue for a prolonged period. Shankar discloses a method for detecting cancer cells comprising administering 123I or 131I to subjects with thyroid cancer. [Shankar, Abstract]
123I remained detectable at the tumor site 24 hours after administration. 131I remained detectable at the tumor site seven days after administration. [Shankar, Figure 3, 4] Shankar further discloses that the images obtained at 24 hours were superior to the images taken at 5 hours.
Taken together, it is not surprising that a conjugate comprising 89Zr or any detectable label that is known to accumulate at tumor sites for a prolonged period would be able to achieve the aforementioned advantageous property. Therefore, Applicant’s allegations of unexpected results are not persuasive, at least because the results are not commensurate in scope with the claims and are not, in fact, unexpected.
Cornelis (Long–Half-Life 89Zr-Labeled Radiotracers Can Guide Percutaneous Biopsy Within the PET/CT Suite Without Reinjection of Radiotracer, The Journal of Nuclear Medicine, Vol. 59, No. 3, March 2018); Abou (In Vivo Biodistribution and Accumulation of 89zr in Mice, Nucl Med Biol. 2011 July; 38(5): 675–681); Shankar (Comparison of 123I Scintigraphy at 5 and 24 Hours in Patients with Differentiated Thyroid Cancer, The Journal of Nuclear Medicine, Vol. 43, No. 1, January 2002).
Conclusion
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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