DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 1, 2025 has been entered.
Claims 40-58 are pending. Claims 40, 41, and 44 are amended. Claims 57 and 58 are new. Claim 43 remains withdrawn. Claims 40-42, 44-58 are currently being examined as drawn to the elected species of:
A. (a) only VEGF biomarker; and
B. (a) treatment regimen further comprising an agonist of a VEGF-signaling pathway (claim 44).
New Rejection
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
2. Claims 40-42 and 44-58 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature/ a natural phenomenon) without significantly more. The claim(s) recite(s) the steps of:
(a) receiving a measurement of baseline level of at least one biomarker, VEGF, in a first test sample from a patient with melanoma before undergoing treatment comprising sorafenib; and receiving a measurement of an interim level of at least one biomarker, VEGF, in a second test sample obtained from the patient after undergoing the treatment;
(b) comparing or having compared the baseline level of the at least one biomarker to the interim level;
(c) continuing administration of the treatment to the patient when in step (b) the interim level of VEGF is higher than the baseline level;
(d) modifying administration of the treatment to the patient when in step (b) the interim level of VEGF is lower than the baseline level.
Claim 54 recites the modifying step (d) encompasses increasing the dosage of sorafenib, the frequency of administration of sorafenib, the route of administration of sorafenib, or a combination thereof.
Claims 55 and 57 recite the modifying step (d) encompasses discontinuing treatment when the level of VEGF is lower than the baseline level.
Claims 45-53 recite that the step (a) of receiving a measurement of baseline and interim VEGF levels comprises an immunoassay utilizing multi-well assay plate, plurality of electrodes, and detectable ECL labels.
Thus, the claims are directed to the judicial exception of naturally occurring levels of VEGF in melanoma patients in response to sorafenib treatment. This judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature without applying the data to a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite use of routine laboratory procedures to detect and observe naturally occurring levels of VEGF. The steps of immunoassay using multi-well assay plate, electrodes, ECL labels, and solid particle substrate detection as claimed, are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception (see MPEP 2106.05(d)). For example, Escudier et al (Cancer Therapy 2007, 13:1801-1809) teaches measuring, by commercial ELISA kit, the level of a plurality of biomarkers including VEGF at baseline and interim levels of sorafenib treatment, including form a melanoma patient (see prior art rejection below). WO 2010/0127057, Glezer et al teaches known immunoassays for measuring VEGF levels in a patient test sample in order to assess changes in VEGF levels during sorafenib treatment relative to baseline; the immunoassay comprising a commercially available multi-well, multi-spot MSD® electrochemiluminescent (ECL) assay (MSD MULTI-SPOT® plate) that comprises a cartridge and is able to detect multiple biomarkers in a single test reaction including VEGF using ECL label and a plurality of electrodes. Glezer also teaches known immunoassays utilizing particles having antibodies immobilized to them for detection of proteins such as the Luminex® system, or magnetic particles for flow cytometry (see prior art rejection below). Deiss et al (Journal of the American Chemical Society, 2009, 131:6088-6089) teaches and exemplifies known multiplexed immunoassays detecting biomarkers including VEGF in biological samples, utilizing microbeads as support particles, detection antibodies immobilized to the beads, detectably labeled antibodies to bind VEGF and biomarkers, and electrogenerated chemiluminescence (ECL) as a readout mechanism to detect multiple antigens simultaneously (see entire paper and Figures 1-3). Ascierto et al (Anticancer Research, 2004, 24:4255-4258) teach measuring serum VEGF levels in melanoma patients at baseline and multiple time points after therapy utilizing commercially available Human VEGF Immunoassay Quantikine™ (R&D Systems), which is a quantitative sandwich enzyme immunoassay (Patients and Methods). Domnanich et al (Sensors and Actuators B: Chemical, 2009, 139:2-8) teaches an immunoassay comprising a protein microarray platform (chip-based sandwich immunoassay) for the parallel analysis of five melanoma serum biomarker proteins including VEGF, wherein levels of VEGF are known to be increased in progressing stages of melanoma (see entire paper and Table 1). Routine data gathering in order to observe a natural phenomenon/ natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/ natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc.
The instantly claimed step of “(d) modifying administration of the treatment regimen to the patient” by discontinuing treatment after observing a decreased VEGF interim level (claims 40, 55 and 57) is claiming an inaction, where there is no particular treatment applied and no step further performed. Therefore, there is no practical application of the observed judicial exception in methods where patients have decreased interim levels of VEGF.
The instantly claimed step of “(c) continuing administration of the treatment regimen (sorafenib) to the patient” when the interim level of VEGF is higher than baseline level (claims 40, 57) is simply appending well-understood, routine, conventional activity of continuing the same treatment while continuing to observe changes in naturally occurring levels of VEGF biomarker. It is a limitation that is well-understood, routine, conventional activity in the field of treating melanoma and observing biomarker levels during treatment and does not amount to significantly more than the judicial exception (see MPEP 2106.05(d)). This step does not apply or use the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to observe treatment response (see MPEP 2106.05(e)). This step does not add any specific limitation other than what was already occurring before observation of interim levels of VEGF. This step is considered to be adding insignificant extra-solution activity to the judicial exception by reciting generic methods of administering more of the same treatment (see MPEP 2106.05(g)).
The instantly claimed step of “(d) modifying administration of the treatment regimen to the patient” when the interim level of VEGF is lower than baseline level, wherein modification is increasing dosage of sorafenib, the frequency of administration of sorafenib, the route of administration of sorafenib, or combination thereof (claims 40, 54, 58), is simply appending well-understood, routine, conventional activity of performing any generic non-specific modification (claim 40(d)), or continuing the same treatment by a non-specific dose increase, non-specific frequency of administration change, or a non-specific change in route of administration (claims 54, 58). It is a limitation that is well-understood, routine, conventional activity in the field of treating melanoma and observing biomarker levels during treatment. Altering the administration regimen of the same drug (sorafenib) in a non-specific manner does not amount to significantly more than the judicial exception (see MPEP 2106.05(d)). This step does not apply or use the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to observe treatment response (see MPEP 2106.05(e)). This step does not add any specific limitation or novel treatment regimen above and beyond, or significantly more, than what was already occurring before observation of interim levels of VEGF. This step is considered to be adding insignificant extra-solution activity to the judicial exception by reciting generic methods of administering more of the same treatment (see MPEP 2106.05(g)).
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
3. Claims 40, 42 45, 54, 56-58 remain/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Escudier et al (Cancer Therapy 2007, 13:1801-1809).
Escudier teaches a method of administering a sorafenib treatment regimen to a patient having renal cell carcinoma or melanoma, the method comprising:
(a) measuring, by commercial ELISA kit, the level of a plurality of biomarkers including VEGF at baseline, on day 1 (baseline) and day 15 of treatment cycle 1; day 1 of cycles 2, 4, and 7, and at study end of treatment comprising sorafenib, wherein measurement occurs in patient test samples (p. 1804, col. 1-2);
(b) comparing the levels of the plurality of biomarkers including VEGF with each time point taken to identify increases or decreases in levels during treatment (p. 1804, col. 1-2p. 1806, col. 1-2);
(c) wherein a trend was observed toward increased levels of cytokines, VEGF and IL-6 up relative to baseline to cycle 2 (~ 8 weeks), and VEGF levels declined relative to baseline levels during the remaining 20 weeks of treatment (p. 1806, col. 2; see Figure 5C and D below). Figures 5C and D represent the mean values for 12 patients tested.
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Escudier teaches continued treatment with sorafenib resulted in stable disease for 61.5% of treated patients, including the melanoma patient (Figure 2; p. 1805, col. 2 last paragraph). Escudier explains that the initial rise in VEGF levels during treatment is likely due to a vascular disruption by sorafenib and increased in levels of intratumoral hypoxia are known to be associated with VEGF levels (p. 1808, col. 2). Thus, Escudier demonstrates VEGF levels initially rise relative to baseline levels during sorafenib treatment.
Escudier teaches the patients tested for VEGF levels encompassed those receiving different doses of sorafenib at either 400 mg b.i.d. or 200 mg b.i.d., and either dose encompassed patients with stable disease and evidence of tumor shrinkage (Figure 2; p. 1805, col. 2 “Efficacy”).
Escudier does not teach the steps of analysis and determination of increased VEGF levels compared to baseline levels in a melanoma patient occurred before continuing sorafenib therapy (claim 40 (c); claim 57).
Escudier determined interim levels of VEGF eventually decreased compared to baseline levels in a responsive melanoma patient but does not teach subsequently increasing the dose or modifying the frequency of sorafenib administration (claims 40(d), 54, 58).
Escudier does not teach repeating steps (a)-(c) above followed by continuing sorafenib treatment or increasing the dose or frequency of sorafenib treatment, one or more times (claim 56).
Continue administration of sorafenib after determining an increase in VEGF levels in a patient sample compared to baseline levels:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to continue administration of sorafenib after determining an increase in VEGF levels in a patient sample compared to baseline levels. One would have been motivated to because Escudier teaches testing biomarker levels including VEGF repeatedly through continuation of sorafenib treatment of the melanoma patients in order to observe and identify the effect of sorafenib on VEGF levels during treatment. One of ordinary skill in the art would have a reasonable expectation of success continuing sorafenib treatment when VEGF levels are higher during treatment compared to baseline levels because: (1) Escudier demonstrates that VEGF levels typically rise during treatment initially and continued sorafenib treatment resulted in stable disease for 61.5% of treated patients, including the melanoma patient; and (2) Escudier explains the mechanism for rise in VEGF levels during treatment can be attributed to a vascular disruption by sorafenib and increased in levels of intratumoral hypoxia. Given the disclosure provided by Escudier, it is well within the level of the ordinary skilled artisan to continue administering sorafenib to melanoma patients as their VEGF levels rise relative to baseline, and treat melanoma.
Increase the dose or change frequency of sorafenib administration for the responsive patient demonstrating decreased interim levels of VEGF compared to baseline:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to increase the dose or change frequency of sorafenib administration for the responsive patient demonstrating decreased interim levels of VEGF compared to baseline. One would have been motivated to because: (1) Escudier teaches testing biomarker levels including VEGF repeatedly through sorafenib treatment of the melanoma patient and other cancer patients, in order to observe and identify the effect of sorafenib on VEGF levels through treatment, wherein VEGF levels typically decrease below baseline during sorafenib treatment; and (2) Escudier teaches the cancer patients tested received low or high doses of sorafenib encompassing 200 mg or 400 mg, wherein the melanoma patient received 200 mg and had stable disease, and wherein cancer patients on either dose demonstrated stable disease and tumor shrinkage. One of ordinary skill in the art would have a reasonable expectation of success continuing sorafenib treatment by increasing dose or frequency of administration for a patient demonstrating decreased interim levels of VEGF compared to baseline because Escudier demonstrates that patients responsive to sorafenib treatment typically display decreasing levels of VEGF compared to baseline as treatment continues, and demonstrate successful cancer treatment with various doses of sorafenib. Given Escudier demonstrated that: (1) cancer/melanoma patients typically display decreasing levels of VEGF compared to baseline as sorafenib treatment continues, (2) either high or low doses of sorafenib result in the same VEGF trend; and (3) administering sorafenib treatment, including at higher or lower doses, successfully treated cancer in such patients, one of skill in the art could have pursued administering more of the same successful drug at higher doses or altered/increased frequency to a patient demonstrating typical decreased levels of VEGF compared to baseline, and predictably treated the melanoma patient.
Repeat steps (a)-(c) above followed by continuing sorafenib treatment or increasing the dose or frequency of sorafenib treatment, one or more times:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to repeat steps (a)-(c) above followed by continuing sorafenib treatment or increasing the dose or frequency of sorafenib treatment, one or more times in the method of Escudier. One would have been motivated to because Escudier teaches testing biomarker levels including VEGF repeatedly through sorafenib treatment of the melanoma patient and other cancer patients, in order to observe and identify the effect of sorafenib on VEGF levels through treatment, including in response to different doses of sorafenib. One of ordinary skill in the art would have a reasonable expectation of success repeating VEGF testing through treatment, and continuing treatment or modifying treatment given Escudier demonstrates successfully measuring and comparing VEGF levels through continued sorafenib treatment of patients receiving different doses of sorafenib. Given the motivation provided by Escudier to measure and compare changes in VEGF levels throughout sorafenib treatment of cancer patients, and the success demonstrated by Escudier for doing so, including for patients receiving different doses of sorafenib, it is well within the level of a skilled artisan to repeat assaying VEGF levels through sorafenib treatment that comprises more of the same dose or a changed dose.
4. Claim 44 remains rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Escudier et al (Cancer Therapy 2007, 13:1801-1809); as applied to claims 40, 42 45, 54, 56-58 above, and further in view of Lev et al (Molecular Cancer Therapeutics, 2003, 2:753-763), and Hauschild, A., Kähler, K.C., Egberts, F. (2009). Sorafenib, a Multikinase Inhibitor: Results from Clinical Trials in Melanoma Patients. Chapter 47, pages 565-574 in: Leong, S. (eds) From Local Invasion to Metastatic Cancer. Current Clinical Oncology. Humana Press, Totowa, NJ.
Escudier teaches a method of administering a treatment comprising sorafenib to a melanoma patient, the method comprising measuring and comparing levels of VEGF in patient test samples at baseline and during treatment, and continuing treatment when VEGF levels are higher than baseline, as set forth above.
Escudier further teaches that sorafenib treatment is known to be combined with different anti-cancer agents including dacarbazine. Escudier teaches combining sorafenib with drugs that have different mechanisms of action may help to maximize its therapeutic potential and overcome tumor resistance, which commonly limits effectiveness of monotherapies (p. 1808, col. 1).
Escudier teaches sorafenib has been combined with dacarbazine but does not exemplify doing so to treat melanoma.
Lev teaches dacarbazine (DTIC) is the gold standard for metastatic melanoma treatment, having a response rate of 15-20%, however resistance to therapy develops (abstract). Lev teaches (p. 753, col. 2):
“Numerous chemotherapeutic agents have shown some activity in the treatment of malignant melanoma with DTIC4 being the most widely used. DTIC is a nonclassical alkylating agent, generally considered the most active agent for treating malignant melanoma and is approved by the U. S. Food and Drug Administration for this purpose.”
Lev teaches that resistance to DTIC therapy is a problem and suggest combining therapies with DTIC to overcome it (p. 753, col. 2 to p. 754, col. 1):
“However, response rates for single-agent DTIC are disappointing, ranging from 10 to 25%, with complete responses seen in _5% of patients. In addition, the response duration is often brief, i.e., 5–6 months (11, 12). A major obstacle to a successful treatment of metastatic melanoma is its notorious resistance to chemotherapy (13– 15)…. In the meantime, chemotherapy will remain the treatment of choice, and strategies to overcome resistance offer a more immediate possibility for improving the lot of these patients. Exploring the mechanisms of overcoming tumor resistance to DTIC are therefore of great interest.”
Lev teaches that DTIC is a VEGF agonist, increasing VEGF levels which contributes to melanoma chemotherapeutic resistance and allows melanoma cells to evade death. Lev suggests combining DTIC therapy with an anti-VEGF therapeutic for the treatment of melanoma (p. 754, col. 1-2):
“We hypothesized that resistance to DTIC is a result of increases in IL-8 and VEGF production in response to the drug. Here, we analyze the effect of DTIC on the production of IL-8 and VEGF in human melanoma cells. We found that treatment of melanoma cells with DTIC resulted in up-regulation of the proangiogenic cytokines IL-8 and VEGF. We propose that overproduction of these molecules is a potential mechanism for melanoma cells to evade cell death and become resistant to chemotherapy. These data have a significant clinical relevance, justifying the combination of conventional chemotherapy with anti-IL-8 and/or anti-VEGF modalities for the treatment of malignant melanoma.”
Lev demonstrates that DTIC treatment of melanoma cells results in an increase in VEGF levels (Figure 2; Table 1; p. 759, col. 1, Discussion).
Like Escudier, Lev teaches that it is known that in the tumor microenvironment hypoxia leads to a rapid increase in VEGF levels (p. 760, col. 1):
“VEGF and IL-8 are known to be inducible in tumor cells in response to various stimuli derived from the tumor microenvironment, of which, hypoxia is the best characterized (38, 39). Hypoxia leads to a rapid increase in VEGF and IL-8
expression in numerous cells both by increasing the transcription of the gene and by prolonging mRNA half-life.”
Hauschild teaches sorafenib inhibits VEGF receptors (Table 1; section 2), but appears to have limiting single-agent therapeutic function in metastatic/advanced melanoma (abstract; section 4). Hauschild cites Lev (above) and teaches “the rationale to combine DTIC with sorafenib is that DTIC treatment had been demonstrated to upregulate VEGF expression in melanoma cells in vitro (p. 569, section 5). Hauschild teaches clinical application of sorafenib combined with DTIC to melanoma patients successfully increased progression-free survival (PFS), for DTIC + sorafenib compared to DTIC alone (section 5; Table 2 on p. 571).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine DTIC with sorafenib in the method of treating melanoma patients taught by Escudier. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Escudier, Lev, and Hauschild teach DTIC and sorafenib are known agents for the treatment of melanoma, teach the common development of resistance to single agent sorafenib or DTIC therapy, and teach the need to provide combination therapy to overcome resistance; (2) Escudier demonstrates that VEGF levels rise initially during therapy with sorafenib then decrease as treatment continues, whereas Lev and Hauschild teach DTIC therapy results in increasing VEGF levels in melanoma and suggest there is a need to combine DTIC with ant-VEGF therapy such as sorafenib; (3) Hauschild demonstrates clinical treatment of melanoma patients with combined sorafenib and DTIC, wherein the combination treatment resulted in improved PFS compared to single agent therapy.
Given the importance of monitoring VEGF during DTIC or sorafenib treatment, and the role VEGF plays in melanoma progression, as taught by the cited prior art, one would have been motivated to monitor VEGF levels during continued treatment with the combination DTIC + sorafenib treatment. Given the known successful methods for measuring VEGF during either therapy, one of skill in the art could have pursued monitoring VEGF expression levels during combination therapy and reasonably expected to see an initial increase in VEGF levels after treatment as compared to baseline and continued combination therapy with a reasonable expectation of success.
5. Claim 41, 46-53 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Escudier et al (Cancer Therapy 2007, 13:1801-1809); as applied to claims 40, 42 45, 54, 56-58 above, and further in view of WO 2010/0127057, Glezer et al.
Escudier teaches a method of administering a treatment comprising sorafenib to a melanoma patient, the method comprising measuring and comparing levels of VEGF in patient test samples at baseline and during treatment, and continuing treatment when VEGF levels are higher than baseline, wherein VEGF measurement was conducted using a commercially available ELISA, as set forth above.
Escudier does not teach the immunoassay comprises a multiplexed assay measurement comprising a plurality of biomarkers; multi-well assay plate; cartridge; plurality of electrodes; measuring ECL labels, or particles with antibodies immobilized on them.
Glezer teaches an immunoassay for measuring VEGF levels in a patient test sample in order to assess changes in VEGF levels during sorafenib treatment relative to baseline; the immunoassay comprising a commercially available multi-well, multi-spot MSD® electrochemiluminescent (ECL) assay (MSD MULTI-SPOT® plate) that comprises a cartridge and is able to detect multiple biomarkers in a single test reaction including VEGF using ECL label and a plurality of electrodes (p. 3-9 and 14-20; Examples, Table 1; claims 1-3, 5, 7, 12-16, 18-19, 23-30). Glezer also teaches known immunoassays utilizing particles having antibodies immobilized to them for detection of proteins such as the Luminex® system, or magnetic particles for flow cytometry (p. 15-16).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to utilize a commercially available MSD MULTI-SPOT® plate and ECL detection or particles having immobilized antibodies on them for the detection of the one or more biomarkers comprising VEGF in the method of Escudier. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Escudier teaches using a commercially available ELISA to detect VEGF levels during sorafenib treatment, including comparing baseline VEGF levels with VEGF levels detected during therapy; (2) Glezer also teaches detecting changes in VEGF levels compared to baseline in cancer patients treated with sorafenib using immunoassays and suggests utilizing MSD MULTI-SPOT® plate and ECL detection or using known particles having immobilized antibodies on them for the detection of one or more biomarkers comprising VEGF; and (3) Glezer successfully exemplifies using MSD MULTI-SPOT® plate and ECL detection to monitor levels of VEGF in cancer patient samples during sorafenib treatment.
6. Claims 55 and 57 remain/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Escudier et al (Cancer Therapy 2007, 13:1801-1809); as applied to claims 40, 42 45, 54, 56-58 above, and further in view of Eisen et al (British Journal of Cancer, 2006, 95:581-586).
Escudier teaches a method of measuring and comparing baseline and treatment levels of VEGF in a melanoma patient during sorafenib treatment, measuring patient response to treatment, measuring tumor size response to treatment, determining the trend of VEGF levels decreasing compared to baseline levels as treatment continues, and continuing sorafenib treatment or modifying treatment, as set forth above. Escudier demonstrates that despite the overall trend of VEGF levels decreasing from baseline after sorafenib treatment, some patients progressed in disease and had increased tumor growth (Figure 2).
Escudier does not teach the modification comprises discontinuing sorafenib treatment when the interim level of VEGF is lower than the baseline level (claims 55 and 57).
Eisen teaches treatment of melanoma patients with sorafenib and measuring and comparing tumor size between baseline and 12 weeks of treatment, wherein patients with ≥25% tumor shrinkage continued sorafenib treatment, and patients with ≥25% tumor growth discontinued sorafenib treatment because their tumors were not responding (abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to discontinue sorafenib treatment for patient having decreasing VEGF levels and increasing tumor growth in the method of Escudier. One would have been motivated to because: (1) Escudier demonstrates that despite the overall trend of VEGF levels decreasing below baseline levels after continued sorafenib treatment, some cancer patients progressed with increased tumor growth; and (2) Eisen teaches discontinuing sorafenib treatment for patients whose tumors demonstrate increasing tumor growth and demonstrate disease progression because of their lack of response to therapy. One would have a reasonable expectation of success to stop cancer therapy when a patient’s VEGF levels have expectedly decreased below baseline after continued sorafenib treatment, and when their disease progresses and tumor size increases, in view of the patient’s cancer no longer responding, as demonstrated by Eisen.
Response to Arguments for 35 U.S.C. 103(a) Rejections
7. Applicants argue that Escudier does not lead to a reasonable expectation of success using the claimed method. Applicants argue that Escudier measures VEGF levels in response to sorafenib treatment in RCC and melanoma patients but does not use this information to inform or modify the treatment regimen as required by steps (c) and (d) of the claimed method.
Applicants argue that Escudier observes VEGF levels with no suggestion to modify treatment regimen. Applicants argue that Esciudier does not provide for a predictable result as claimed.
8. The arguments have been considered but are not persuasive. Although claim 40 recites the method comprises steps (c) and (d), these steps are mutually exclusive and cannot occur simultaneously when practicing the claimed method for a patient. According to the claimed method, only one of two outcomes can occur: (1) the patient’s interim level of VEGF is higher than baseline level and administration of sorafenib treatment regimen is continued; OR (2) the patient’s interim level of VEGF is lower than baseline level and administration of sorafenib treatment regimen is modified. The method cannot continue the sorafenib treatment regimen and modify the treatment regimen in a single melanoma patient at the same time. Steps (c) and (d) are alternative outcomes and treatments. Only one outcome and one treatment at a time can occur when practicing the method as claimed, and Escudier renders obvious a method having either outcome and treatment for the reasons of record. Similar logic applies to the two outcomes claimed in new claim 57.
It is further pointed out that the instant claims recite completely opposite treatment modifications for the same VEGF result, that is, when the interim level of VEGF is lower than the baseline level, either: (1) modify treatment to increase the dosage of sorafenib, or to increase frequency of sorafenib treatment (claim 54, 58), or (2) modify the treatment by discontinuing administration of sorafenib (claim 55 and 57). Escudier renders obvious treatment modification (1) above for the reasons of record, and Escudier combined with Eisen render obvious treatment modification (2) above for the reasons of record.
Although Applicants argue that Escudier did not teach using VEGF levels to make a clinical decision on continuing or modifying sorafenib treatment, the arguments are not persuasive because the motivation provided by the cited prior art to arrive at the claimed invention does not need to be the same as Applicant’s motivation.
MPEP 2144 states: The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon,, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
In the instant case, Escudier measured VEGF levels from baseline through sorafenib treatment to observe biological response of VEGF levels to sorafenib treatment, and Escudier described VEGF as a proangiogenic biomarker (p. 1804, col. 2) that is a known target of sorafenib (p. 1801, col. 2). Escudier provides motivation to observe the demonstrated trend of initially increasing VEGF levels and to observe the demonstrated trend of subsequently decreasing VEGF levels during sorafenib treatment, in order to test the effects of sorafenib treatment on its known target: VEGF. Escudier also provides motivation to observe these trends in VEGF levels when administering different sorafenib doses, including high (400 mg) and low (200 mg) sorafenib doses that were demonstrated to successfully treat cancer patients. Given Escudier demonstrated that either sorafenib dose successfully treated cancer patients, and either dose demonstrated the trends of initial increase in VEGF levels above baseline, and subsequent decease in VEGF levels below baseline, one of skill in the art could have successfully increased the amount or frequency of sorafenib dose after continued treatment when VEGF levels decreased (i.e., administered more of the same drug known and demonstrated to successfully treat cancer), and predictably result in cancer treatment. Contrary to arguments, Escudier does provide for a predictable result of treating melanoma by administering sorafenib continuously while levels of VEGF rise above baseline, and to administer an increased dose after VEGF levels fall below baseline.
9. Applicants argue that Escudier teaches there was a non-significant trend in VEGF levels upon co-administration of sorafenib and interferon alpha-2a, pointing to p. 1808, col. 2. Applicants argue that given the non-significance of the results, the fact the patient population is heavily weighted to RCC patients, and the fact the results are in response to a combined therapy, one would not be able to practice the claimed methods on the claimed melanoma subjects with a reasonable expectation of success because no conclusions can be drawn from Escudier’s data.
10. The arguments have been considered but are not persuasive. Escudier included a melanoma patient’s results with the RCC patients’ results because Escudier considers their sorafenib responses to be similar, therefore the results taught by Escudier are expected for melanoma patients, even if the majority of patients tested were RCC patients. Applicants have not provided evidence that the melanoma + RCC patient data presented by Escudier would not be applicable to melanoma patients, or that Escudier taught otherwise.
Escudier’s scientific characterization of increasing plasma VEGF and IL-6 levels observed during the first 8 weeks as a statistically non-significant trend, does not negate Escudier’s observation and disclosure of increased interim levels of VEGF initially, followed by subsequent decreased levels of VEGF during sorafenib treatment, all while continuing successful sorafenib treatment. Further, Escudier provides a scientific explanation of why these trends occurred in response to sorafenib treatment:
“In the present study, a nonsignificant trend toward increasing plasma VEGF and IL-6 was observed during the first 8 weeks, which was subsequently followed by a decline in levels of these cytokines. The precise mechanism of how sorafenib affects plasma VEGF levels is currently unknown. However, it is conceivable that vasculature disruption by sorafenib could explain the initial elevation of VEGF levels over the first 8 weeks, as it could lead to increased levels of intratumoral hypoxia. Studies have shown that a significant correlation exists between serum VEGF levels and the number of platelets (45).”
Additional teachings in Escudier summarized in the rejection of record provide motivation and reasonable expectation of success to continue administrating sorafenib when levels of VEGF increase compared to baseline, and to administer higher or variable doses of sorafenib when observing decreased interim levels of VEGF. The Escudier reference as a whole, provides motivation and reasonable expectation of success to arrive at the instantly claimed invention. As stated in the rejection:
Continue administration of sorafenib after determining an increase in VEGF levels in a patient sample compared to baseline levels:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to continue administration of sorafenib after determining an increase in VEGF levels in a patient sample compared to baseline levels. One would have been motivated to because Escudier teaches testing biomarker levels including VEGF repeatedly through continuation of sorafenib treatment of the melanoma patients in order to observe and identify the effect of sorafenib on VEGF levels during treatment. One of ordinary skill in the art would have a reasonable expectation of success continuing sorafenib treatment when VEGF levels are higher during treatment compared to baseline levels because: (1) Escudier demonstrates that VEGF levels typically rise during treatment initially and continued sorafenib treatment resulted in stable disease for 61.5% of treated patients, including the melanoma patient; and (2) Escudier explains the mechanism for rise in VEGF levels during treatment can be attributed to a vascular disruption by sorafenib and increased in levels of intratumoral hypoxia. Given the disclosure provided by Escudier, it is well within the level of the ordinary skilled artisan to continue administering sorafenib to melanoma patients as their VEGF levels rise relative to baseline, and treat melanoma.
Increase the dose or frequency of sorafenib administration for the responsive patient demonstrating decreased interim levels of VEGF compared to baseline:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to increasing the dose or frequency of sorafenib administration for the responsive patient demonstrating decreased interim levels of VEGF compared to baseline. One would have been motivated to because: (1) Escudier teaches testing biomarker levels including VEGF repeatedly through sorafenib treatment of the melanoma patient and other cancer patients, in order to observe and identify the effect of sorafenib on VEGF levels through treatment, wherein VEGF levels typically decrease below baseline during sorafenib treatment; and (2) Escudier teaches the cancer patients tested received low or high doses of sorafenib encompassing 200 mg or 400 mg, wherein the melanoma patient received 200 mg and had stable disease, and wherein cancer patients on either dose demonstrated stable disease and tumor shrinkage. One of ordinary skill in the art would have a reasonable expectation of success continuing sorafenib treatment by increasing dose or frequency of administration for a patient demonstrating decreased interim levels of VEGF compared to baseline because Escudier demonstrates that patients responsive to sorafenib treatment typically display decreasing levels of VEGF compared to baseline as treatment continues, and demonstrate successful cancer treatment with various doses of sorafenib. Given Escudier demonstrated that: (1) cancer/melanoma patients typically display decreasing levels of VEGF compared to baseline as sorafenib treatment continues, (2) either high or low doses of sorafenib result in the same VEGF trend; and (3) administering sorafenib treatment, including at higher or lower doses, successfully treated cancer in such patients, one of skill in the art could have pursued administering more of the same successful drug at higher doses or increased frequency to a patient demonstrating typical decreased levels of VEGF compared to baseline, and predictably treated the cancer patient.
The fact that the results of Escudier are based on co-administration of sorafenib with IFN does not teach away from the invention, and the instant claims do not exclude the results or methods taught by Escudier. The instant claims recite that the treatment regimen comprises sorafenib, indicating the treatment regimen broadly encompasses other therapeutic agents in addition to sorafenib. Claim 44 supports this interpretation, claiming the treatment regimen comprises administering an agonist of VEGF-signaling pathway in addition to sorafenib. Therefore, the method of Escudier administering a treatment regimen comprising sorafenib is not excluded by the claims.
11. Applicants argue there is no reasonable expectation of success for a rationale of “obvious to try” because Escudier does not provide a reasonable expectation of success for VEGF to be used as a biomarker to monitor efficacy and adjust treatment accordingly as claimed.
12. The arguments have been considered but are not persuasive. In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, Escudier recognizes that sorafenib targets and reduces angiogenesis, that VEGF is a biomarker of angiogenesis, and teaches it is established that in “two human melanoma xenograft models, sorafenib inhibited tumor growth by blocking tumor cell VEGF production, resulting in antiangiogenic, antiproliferative, and apoptotic effects” (p. 1801, col. 2 to p. 1802, col. 1; p. 1806, col. 1 at top). Therefore, VEGF is an established angiogenic biomarker and target of sorafenib. Escudier recognized the need to assess the effects of sorafenib treatment, and at different doses, on interim VEGF levels and other proangiogenic markers in RCC and melanoma patients, and to correlate the results to patient treatment outcome. Escudier provided a finite solution of administering different sorafenib treatment regimens (dose escalations) to the cancer patients and measuring subsequent, changing levels of VEGF angiogenic biomarker in response to sorafenib treatment, and correlating biomarker changes to treatment response. Given Escudier teaches: (1) the need to determine the effect of various sorafenib treatment regimens on angiogenic marker VEGF levels and treatment outcome, and (2) the successful methods for carrying out repeated measurement of VEGF levels at baseline and interim during sorafenib treatment, and determining that VEGF levels both rise and fall during the different sorafenib doses and during continued treatment, all resulting in an outcome of stable disease; one of skill in the art could have pursued administering a different/higher dose of sorafenib or continuing sorafenib treatment after seeing a rise or fall in VEGF levels, and to continue administration of sorafenib at the current dose or different does and successfully treat melanoma while observing VEGF biomarker interim levels, and with a reasonable expectation of success.
13. Applicants argue the instant specification, unlike Escudier, supports use of VEGF as a marker to track/modify treatment of melanoma patients with sorafenib and point to Table 5, pages 30-31.
Applicants argue the data demonstrates mice harboring tumor xenografts with two melanoma cell lines A375 and SKMEL5 have increased levels of VEGF after sorafenib treatment.
14. The arguments have been considered but are not persuasive. The mouse xenograft data in the specification pointed to by Applicants does not provide results that are superior to or unexpected over the methods and clinical results taught by Escudier. Therefore, the mouse xenograft data of the instant specification does not render the invention non-obvious over what is taught and expected by the cited prior art.
15. Applicants argue the secondary references, Lev, Hauschild, and/or Glezer fail to remedy these deficiencies.
16. The arguments have been considered but are not persuasive. Escudier does not have the deficiencies argued by Applicants for the reasons stated above, therefore the secondary references need not remedy those deficiencies argued.
17. Applicants did not specifically address Esiner.
18. All other objections recited in the Office Action mailed March 18, 2025 are hereby withdrawn in view of amendments.
19. Conclusion: No claim is allowed.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642