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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/04/2023 has been entered.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/US2019/029740, filed 04/29/2019, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/664,633, filed 04/30/2018.
Status of the Claims
Claims 38-57 are pending; claims 1-37 are canceled; claims 38, 40-46, 48 and 51-54 are amended; claim 55-57 are withdrawn. Claims 38-54 are subject to examination below.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Drawings filed 10/28/2020 contain drawings in color.
Withdrawn Objections/Rejections
The previous rejection of claims under 35 U.S.C. 112(b) is withdrawn in response to Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 41-46, 48, 51 and 54 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 41 recites “The method of claim 40, further comprising flowing a third buffer comprising capture probe…”, it is unclear from the recited language where/how this additional method steps fits into the method of claim 40 which encompasses the limitations of claim 38. For example, claim 38 recites at the end of the method, steps (e) and (d), detecting observation of a signal, determining bioavailability… in an event signal is observed. However, claim 41 recites “further comprising”, and as presented could encompass this further step following step d, i.e., performed after bioavailability has already been determined. As a result, the metes and bounds of the recited claim language are unclear as it is not clear if this additional limitation at 41 is part of the method performed in order to determine the bioavailability, or rather is an additional step performed after all the steps of claims 38 and 40.
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.
Claim(s) 38-48 are rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al., US PG Pub No. 2013/0295688A1 in view of Grego et al., US PG Pub No. 2014/008729A1 and Ruiz Del Agua US PG Pub No. 2013/028171A1.
Regarding claim 38, Bailey teaches a method of detecting an analyte of interest in a biological sample (e.g., paras 21, 34, 36, 245, 246, 251) comprising: (a) providing a biological sample obtained from a subject (applying a sample for which the presence or absence of the analyte of interest is to be determined, paras 21, 34, 36, 245, 246, 251); (b) contacting the biological sample to an optical sensor comprising a first capture probe, wherein the first capture probe is configured to selectively bind to the analyte of interest in the biological sample (providing an optical sensor (e.g. optical ring resonator) comprising a capture probe attached to a surface of the optical sensor (e.g. optical ring resonator), wherein the capture probe is capable of binding to the analyte of interest to form a complex; applying a sample for which the presence or absence of the analyte of interest is to be determined to the optical sensor (e.g. optical ring resonator) under conditions in which the analyte of interest, when present, and the capture probe bind to form a complex, paras 21, 34, 36, 159, 161, 181, 188, 245, 246, 251); (c) contacting the analyte of interest bound to the first capture probe with a second capture probe, wherein the second capture probe is configured to selectively bind to the analyte of interest in the biological sample (providing an antibody that specifically binds to the complex or analyte, wherein binding between the antibody and the complex or the analyte, when the analyte is bound to the capture probe, alters an optical property of the optical sensor (e.g. optical ring resonator), paras 21, 34, 36, 51, 91, 245, 246, 251); and (d) measuring a change in one or more resonance wavelengths of the optical sensor, wherein detection of a change in the one or more resonance wavelengths is an indication of presence of the analyte of interest in the biological sample (detect and/or measure binding-induced shifts in the resonance wavelength of individual binding events, binding of an antibody to the optical sensor can induce a change in local refractive index, thereby inducing a detectable and/or measurable shift in the resonance wavelength on the optical sensor, paras 21, 34, 36, 39, 110, 160, 200, 245, 246, 251).
Bailey teaches the analyte of interest may be a polypeptide, protein, or antibody (paras 34, 152). Bailey teaches the sample may be a biological material obtained from an organism, such as a sample from a patient (paras 158, 252; i.e., biological sample).
Although Bailey does not clearly state determining a first baseline resonance wavelength for an optical sensor wherein the first baseline comprises flowing a buffer over the optical sensor at a first predetermined time and rate, see Bailey at for example Figure 23, the spectrum shows flowing through a buffer only from time 0 to about 7500 seconds. Figure 23 shows real time sensor response (para [0312]).
Bailey does not teach the analyte of interest is a therapeutic biologic and the biological sample is obtained from a subject previously treated with the therapeutic biologic. Further Bailey does not teach the amended limitations, namely a first step of determining a first baseline comprising flow a first buffer at a predetermined time and rate over the optical sensor, performed prior to the step of contacting the sensor with the sample, and following the sample contacting step, a step of determining a second baseline comprising flowing a second buffer over the first capture probe and optical sensor for a second predetermined time and rate, detecting an observation of signal indicating a shift from the first to the second baseline.
Grego et al. similarly teach a method of determining an analyte (such as, for example, a drug) in a subject’s sample using an optical sensor (abstract, paras, [0016] [0034] and [0072]). See para [0039], Grego teach performing an initial baseline measurement as a reference optical measurement signal. See also para [0071], Grego describe establishing a baseline to account for tests and to correct for instrumental shift. The method of Grego comprises providing a biological sample obtained from the subject, determining a first baseline resonance wavelength for an optical signal by flowing a first buffer over the sensor at a first predetermined rate for a first predetermined time (see para [0072], t0 to t1 only a reference solution is flowed through fluidic structure, producing flat signal), contacting sample to the optical sensor, the sensor comprising first capture probe that selectively binds the analyte in the sample (para [0072], flowing sample fluid through structure from t1 to t2, target analytes become bound to analyte-specific receptors of the sensors), determining a second baseline resonance wavelength for the optical sensor by flowing second buffer over the first capture probe and the optical sensor for a second predetermined period of time and for a second predetermined rate (para [0072], at t2 flow of fluid sample replaced with another flow of buffer solution, see reference at para [0072] to detector readings taken from t2-t3, observing signal that reflects slight reduction in concentrations as some non-tightly bound components are removed by the buffer). See at para [0072], Grego report detecting observation of a signal indicating a shift from the first t the second baseline, Grego determining availability of analyte in the sample upon detection of signal (quantitative measure of target analyte mass or concentration provided).
Grego’s example at para [0072] teaches that second step of flowing buffer as a step that removes non-tightly bound components (after contacting with sample). Grego observes a shift from the first buffer (flat signal) to a second signal representing binding event, and further a slight reduction in signal representing removal of the non-tightly bound components. Overall, Grego’s results show a shift between baseline (buffer flow only) and bound analyte after the second buffer (bound analyte, following removal of non-tightly bound components).
Regarding flow rates, Grego teach controlled flow rates (slow rates) (para [0085]). Grego et al. also teach samples that are fluid sample, including biological fluid samples (para [0035], blood, serum, plasma).
Ruiz Del Agua teaches a concentration of a circulating biological drug, together with, optionally, a concentration of antibodies to the biological drug in a blood sample from a patient suffering from rheumatoid arthritis and being treated with the biological drug is associated with the patient’s response to the treatment with the biological drug (para 20). Ruiz Del Agua teaches this information would allow physicians to follow more closely their patients’ response to treatment and make informed decisions over treatment (para 21).
Ruiz Del Agua teaches a method comprising determining the concentration of a circulating biological drug in a sample from a patient treated with an administration of the biological drug (para 22-23, 44-45). The step of determining is performed at a time t1, corresponding to a time point within the period of time between two successive administrations of the biological drug, for example, day 13 after the day of the prior administration (para 22-23, 34-35). The biological drug may be infliximab, adalimumab, or golimumab (par. 14, 22, 26, 30, 32, 44). Ruiz Del Agua teaches a first capture probe to which the biological drug selectively binds and a second capture probe that selectively binds to the biological drug (e.g., TNF-alpha and antibody to said biological drug, par. 73-74).
Ruiz Del Agua teaches the method comprising: providing a biological sample obtained from a subject previously treated with a therapeutic biologic (para 13-14, 18, 22-23, 34-35); contacting the biological sample to a sensor comprising a first capture probe, wherein the first capture probe is configured to bind to the therapeutic biologic in the biological sample (e.g., TNF-alpha, para 38, 73-74); contacting the therapeutic biologic bound to the first capture probe with a second capture probe, wherein the second capture probe is configured to selectively bind to the therapeutic biologic in the biological sample (e.g., antibody to said biological drug, para 73-74); and measuring a change, wherein detection of a change is an indication of presence of the therapeutic biologic in the biological sample (e.g., par. 38, 73-74).
It would have been prima facie obvious to one having ordinary skill in the art to have modified the method of Bailey et al., in order to performed a first step of determining a baseline for the optical sensor comprising flowing a first buffer for a predetermined time and rate, prior to the step of contacting the sample, and further a step of performing a second baseline comprising flowing a second buffer over the first capture probe and optical sensor for a second predetermined rate and time, detecting an observation of signal shift between the first and second baseline. Regarding flowing the first buffer, one having ordinary skill would have been motivated to perform such steps (flowing first and second buffer in that indicated order) in order to remove lightly or poorly bound components. In particular, regarding optical waveguide based sensors, based both on Bailey, as well as Grego et al., performing a first baseline specifically in order to obtain/establish a reference signal, and further in order to account for instrumental drifts. One having ordinary skill would have a reasonable expectation of success because Bailey (for example as cited above) demonstrate measuring real time signal, first flowing buffer to establish a baseline/reference signal without observing binding.
Further, it would have been obvious to have performed a second baseline (flowing a second buffer following contact with sample), one motivated to perform this additional step with second buffer in order to remove any lightly bound components at the sensor in order to obtain accurate quantitative measure (as in Grego). One having ordinary skill would have a reasonable expectation of success because Grego, like Bailey, is relying on methods comprising measuring using optical waveguide sensor systems, Grego specifically indicating
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bailey in view of Grego such that a biological sample from a subject previously treated with a therapeutic biologic is provided and the first and second capture probes are configured to selectively bind to the therapeutic biologic in the biological sample in order to detect the therapeutic biologic as the analyte of interest, as in Ruiz Del Agua, because detecting the therapeutic biologic would allow physicians to follow more closely their patients’ response to treatment with the therapeutic biologic and make informed decisions over treatment. One having ordinary skill in the art would have a reasonable expectation of success in combining the prior art references because Bailey teaches a method of detecting an analyte in a biological sample from a subject, such as an antibody and is generic to the specific analytes, Grego further teaching examples of analytes including analyte that is drug, and Ruiz Del Agua teaches detecting an antibody biological drug in a biological sample from a subject and is generic to the method of detection.
Regarding claim 39, Bailey in view of Ruiz Del Agua, as detailed above, teaches the subject was administered the therapeutic biologic more than seven days before the sample was provided (concentration of the circulating biological drug in a sample from the patient is determined at a time t1, e.g., day 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 after the day of the prior administration, Ruiz Del Agua, par. 35).
Regarding claims 40, Bailey in view of Grego and Ruiz Del Agua teaches detecting no change or no substantial change in one or more resonance lengths at the optical sensor is an indication of absence of the therapeutic biologic in the biological sample, and is therefore considered an indication of a lack of bioavailability of the therapeutic biologic for the subject. Bailey in view of Ruiz Del Agua teaches the detection of the change in one or more resonance wavelengths at the optical sensor is an indication of presence of the therapeutic biologic in the biological sample, and is therefore considered an indication of bioavailability of the therapeutic biologic for the subject (detect and/or measure binding-induced shifts in the resonance wavelength of individual binding events, binding of an antibody to the optical sensor can induce a change in local refractive index, thereby inducing a detectable and/or measurable shift in the resonance wavelength on the optical sensor, Bailey, par. 39, 110, 160, 200, 21, 34, 36, 245, 246, 251; Ruiz Del Agua, par. 72-74).
Regarding claims 41 and 42, see further Bailey at para [0299] the second antibodies in a buffer, as such the combination of the cited art addresses “third buffer” as claimed, the third buffer comprising the second capture probe that is flowed over the optical sensor with captured therapeutic biologic (see as cited previously above, Bailey teaching flowing a second capture probe). The combination of the cited art above is addressing determining presence or absence of antibody against the therapeutic bound at the sensor surface (see the capture antibody immobilized at the sensor surface and the also the second antibody probe that binds the captured target that is captured by the first antibody).
Regarding claim 43, Bailey in view of Ruiz Del Agua, as detailed above, teaches the therapeutic biologic is infliximab, adalimumab, or golimumab (Ruiz Del Agua, par. 14, 22, 26, 30, 32, 44).
Regarding claim 44, Bailey in view of Grego and Ruiz Del Agua, as detailed above, teaches the first capture probe comprises TNFα (Ruiz Del Agua, e.g., par. 73-74).
Regarding claim 45, Bailey in view of Grego and Ruiz Del Agua teaches the second capture probe comprises an anti-human IgG antibody (Bailey, par. 254; Ruiz Del Agua, par. 74, 51).
Regarding claim 46, Bailey in view of Grego and Ruiz Del Agua teaches the biological sample comprises serum (Bailey, par. 158; Ruiz Del Agua, par. 18, 37).
Regarding claim 47, Bailey in view of Grego and Ruiz Del Agua teaches the subject is human (e.g., Bailey, 252, 258, 260; Ruiz Del Agua, par. 17-18).
Regarding claim 48, Bailey in view of Ruiz Del Agua, as detailed above, teaches the first capture probe comprises TNFα (Ruiz Del Agua, e.g., par. 73-74), the therapeutic biologic comprises infliximab or adalimumab (Ruiz Del Agua, par. 14, 22, 26, 30, 32, 44), and the second capture probe comprises an anti-human IgG antibody (Bailey, par. 254; Ruiz Del Agua, par. 74, 51).
Claim(s) 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al. in view of Grego et al. and Ruiz Del Agua as applied to cl aim 38 above, and further in view of Kaempfer et al., US Patent No. 8,535,672 B2.
Regarding claim 49, Bailey teaches the surface density of the capture probes on the surface can be varied to tune the dynamic range of analyte detection and that the surface of an optical sensor can have a range of capture probes spanning from a single capture probe to a number of capture probes that fully saturates all the available binding sites on the surface (para 197, 199), but fails to specifically teach the amount of the first capture probe attached to the optical sensor is from 10 µg to 300 µg.
As another example of a resonance device sensing surface comprising ligand subject to binding, see Kaempfer et al. at for example col. 18, lines 39-65, col. 19, lines 12-15, 37-45, col. 20, lines 22-27, teaching an amount of immobilized ligand for binding/detection that is 100 µg (immobilized sCD28, other examples immobilized sB7-2 on Biacore sensing device).
Although Bailey fails to specifically teach the amount of the first capture probe attached to the optical sensor is from 10 µg to 300 µg, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value for a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation”. Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. at 458, 105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
In the instant case, the prior art teaches that the surface density of the capture probes on the surface can be varied to tune the dynamic range of analyte detection and that the surface of an optical sensor can have a range of capture probes spanning from a single capture probe to a number of capture probes that fully saturates all the available binding sites on the surface (Bailey, para 197, 199). Further, see Kaempfer as an example in the prior art showing 100µg as an appropriate surface amount of a ligand/binding agent immobilized at a sensing surface/chip device.
Absent unexpected results, it would have been prima facie obvious for one of ordinary skill in the art to have arrived at the claimed amount of the first capture probe attached to the optical sensor of from 10 µg to 300 µg by routine optimization, namely by optimizing/selecting values known in the art to be appropriate, for example, it would have been obvious to have used the amount as disclosed by Kaempfer, shown as a an appropriate coating amount, (100 µg, notably a value that falls within the claimed range). It would have been obvious to have arrived at values within the claimed range by optimizing starting at this disclosed amount by the prior art, in order to uncover the optimum workable ranges of the surface density and amount of the capture probes on the surface of the optical sensor to achieve optimum binding. One having ordinary skill in the art would have a reasonable expectation of success in arriving at the claimed amount of the first capture probe attached to the optical sensor through routine optimization because the prior art discloses varying surface density and amount of the capture probes on the surface specifically for the purpose of tuning the dynamic range of analyte detection and because Kaempfer, by showing immobilization of 100 µg, supports this amount as an appropriate, workable amount.
Claim(s) 50-54 are rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al. in view of Grego et al. and Ruiz Del Agua, as applied to claim 38 above, and further in view of Cho et al., WO2005/074650A2, Miao et al., WO2007/070659A2, Abrams et al., US PG Pub No. 2015/0320880A1 and Barrett et al., US PG pub No. 2016/0060338A1.
Regarding claim 50, Bailey in view of Grego et al. and Ruiz Del Agua teaches contacting a first capture probe attached to an optical sensor with the biological sample comprises flowing the biological sample over the optical sensor (Bailey, para 100, 107). Bailey exemplifies flowing solutions at various flow rates for various amounts of time for binding events (e.g., para 303, 305, 324, e.g., functionalization and detection steps, 5µL/min, additional steps 30 µL/min, other binding steps 30 µL/min, also teaching times of about 35 minutes, about 30 minutes).
Bailey in view of Grego et al. and Ruiz Del Agua fails to specifically teach flowing the biological sample over the optical sensor for a period of time of 3 minutes at a rate of flow of 40 µl/min (claim 50), and further fail to teach the specific durations and flow rates as recited at claims 52-54.
However, notably Grego teaches a method of sensing analytes using an optical sensor, including flowing solution over a sensor surface (e.g., abstract, para 16, 72). Grego teaches controlling the flow rate to allow for taking of optical readings (e.g., para 85).
Although the duration and flow rate of Bailey differ from that which is presently claimed (generally longer durations and slightly different flow rates), see further as examples of optical sensing/flow through binding systems and appropriate flow rates and durations, each of Cho et al., para [0671] teaching flowing sample of binding surface at a flow rate of 50 µl/min for 4-5 min to allow association/binding (Biacore flow through chip/system), Miao et al., para [0607] injecting sample of a surface for association/binding at a rate of 40 µl/min for 4-5 minutes (Biacore flow through chip/system), Abrams et al., para [0440] injecting over a binding surface at a rate of 40µl/min for 4 minutes, and Barrett et al., para [0269], injecting over a binding surface at a rate of 40 µl/min for 10 minutes (SPR flow through chip device/system).
Although Bailey in view of Grego and Ruiz Del Agua fails to specifically teach flowing the biological sample over the optical sensor for a period of time of 3 minutes at a rate of flow of 40 µl/min, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value for a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation”. Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. at 458, 105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
The prior art supports that both contact time and rate is a result effective variable, namely a variable optimizable in order to achieve binding/association between capture ligand and analyte flowed through a chip/device. See as cited above, flow rate may be varied/controlled to allow for reaction or incubation time (Grego, par. 85).
Although Bailey teaches a different flow rate/duration than presently claimed, see further Cho, Maio, Abrams and Barrett, these references teach the same or extremely similar flow rates and durations (flow rates of each for achieving binding are taught as 40µl/min, with durations from 3-5 minutes). Based on these references, and absent unexpected results, it would have been prima facie obvious for one of ordinary skill in the art to have arrived at the claimed time/duration and rate for flowing the biological sample over the optical sensor of a period of time of 3 minutes at a rate of flow of 40 µl/min by routine optimization, namely by optimizing within the art disclosed ranges appropriate for achieving binding/association at a sensor capture surface in a flow through device/system, in order to uncover the optimum workable ranges of the contact time and flow rate. One having ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed time and rate for flowing the sample over the optical sensor through routine optimization because the prior art discloses varying the contact time with assay parameters such as binding kinetics and to limit non-specific binding and varying the flow rates for the purpose of allow for reaction or incubation time, and because these various references in the prior art support that such a flow rate and time was known in the art as appropriate for achieving binding/association. It would have been well within the skill level of the ordinary artisan to optimize by selecting within these known art recognized ranges, known suitable for achieving binding, thereby arriving at the claimed duration and flow rate.
Regarding claims 51-54, Bailey in view of the cited prior art teaches contacting the therapeutic biologic bound to the first capture probe with a second capture probe comprises flowing a buffer comprising the second capture probe over the attached therapeutic biologic (e.g., antibody in buffer such as PBS, Bailey, par. 282, 299). Bailey exemplifies flowing solutions at various flow rates for various amounts of time (e.g., par. 281, 282, 305). Bailey in view of the cited art (Grego and Ruiz Del Agua) fails to specifically teach the specifically claimed durations and flow rates for the steps as recited at claims 51-54.
However, for the same reasons as discussed above, it would have been prima facie obvious to have arrived at the claimed durations and flow rates out of routine optimization of experimental conditions, namely by testing values within and similar to those disclosed by the prior art as discussed in detail above, recognized suitable for the purpose of achieving binding/association to uncover the optimum workable conditions. The prior art supports that it is well within the skill of the ordinary artisan to perform routine experimentation and uncover the optimum workable conditions in terms of duration and flow rate.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1.
For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US Patent 9,921,165
Claims 38-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-21 of U.S. Patent No. 9,921,165 (‘165) in view of Bailey et al., (US PG Pub No. 2013/0295688A1) in view of Grego et al., and Ruiz Del Agua.
Regarding claim 38, ‘165 teaches a method of detecting an analyte of interest in a sample (claim 19) comprising:
(a) providing a sample (applying a sample for which the presence or absence of the analyte of interest is to be determined, claim 19);
(b) contacting the sample to an optical sensor comprising a first capture probe, wherein the first capture probe is configured to selectively bind to the analyte of interest in the sample (providing an optical sensor that comprises a ring resonator, the optical sensor comprising a plurality of capture probes attached to a surface of the ring resonator, wherein the capture probes are capable of binding to the analyte of interest to form complexes; applying a sample for which the presence or absence of the analyte of interest is to be determined to the optical sensor, under conditions in which the analyte of interest, when present, and the capture probes bind to form the complexes, claim 19);
(c) contacting the analyte of interest bound to the first capture probe with a second capture probe, wherein the second capture probe is configured to selectively bind to the analyte of interest in the sample (providing plurality of antibodies that specifically bind to the complexes or analyte, claim 19); and
(d) measuring a change in one or more resonance wavelengths of the optical sensor, wherein detection of a change in the one or more resonance wavelengths is an indication of presence of the analyte of interest in the sample (determining the concentration of the analyte of interest in the sample based on the shift of the resonant wavelength resulting from multiple bound particles at the ring resonator, claim 19).
‘165 fails to specifically teach the analyte of interest is a therapeutic biologic and that the sample is a biological sample obtained from a subject previously treated with the therapeutic biologic. ‘165 also fails to teach determining a first baseline comprising a first buffer at a first predetermined rate and period of time (as recited at step (b)) before the contacting sample to the sensor step, and fails to teach following the contacting step, a step of determining a second baseline resonance wavelength comprising flowing a second buffer at a second predetermined rate and period of time (as recited at step (d)), detecting observation of a signal indicating a shift from the first to the second baseline.
However, see the PG Publication of ‘165 (referred to above under 35 U.S.C. 103 and presently as Bailey et al.), Bailey is as cited in detail previously above, Bailey teaches the analyte of interest may be a polypeptide, protein, or antibody (paras 34, 152). Bailey teaches the sample may be a biological material obtained from an organism, such as a sample from a patient (paras 158, 252; i.e., biological sample).
Although Bailey does not clearly state determining a first baseline resonance wavelength for an optical sensor wherein the first baseline comprises flowing a buffer over the optical sensor at a first predetermined time and rate, see Bailey at for example Figure 23, the spectrum shows flowing through a buffer only from time 0 to about 7500 seconds. Figure 23 shows real time sensor response (para [0312]).
Grego et al. is also as cited previously above, Grego teach a method of determining an analyte (such as, for example, a drug) in a subject’s sample using an optical sensor (abstract, paras, [0016] [0034] and [0072]). See para [0039], Grego teach performing an initial baseline measurement as a reference optical measurement signal. See also para [0071], Grego describe establishing a baseline to account for tests and to correct for instrumental shift. The method of Grego comprises providing a biological sample obtained from the subject, determining a first baseline resonance wavelength for an optical signal by flowing a first buffer over the sensor at a first predetermined rate for a first predetermined time (see para [0072], t0 to t1 only a reference solution is flowed through fluidic structure, producing flat signal), contacting sample to the optical sensor, the sensor comprising first capture probe that selectively binds the analyte in the sample (para [0072], flowing sample fluid through structure from t1 to t2, target analytes become bound to analyte-specific receptors of the sensors), determining a second baseline resonance wavelength for the optical sensor by flowing second buffer over the first capture probe and the optical sensor for a second predetermined period of time and for a second predetermined rate (para [0072], at t2 flow of fluid sample replaced with another flow of buffer solution, see reference at para [0072] to detector readings taken from t2-t3, observing signal that reflects slight reduction in concentrations as some non-tightly bound components are removed by the buffer). See at para [0072], Grego report detecting observation of a signal indicating a shift from the first t the second baseline, Grego determining availability of analyte in the sample upon detection of signal (quantitative measure of target analyte mass or concentration provided).
Grego’s example at para [0072] teaches that second step of flowing buffer as a step that removes non-tightly bound components. Grego observes a shift from the first buffer (flat signal) to a second signal representing binding event, and further a slight reduction in signal representing removal of the non-tightly bound components. Overall, Grego’s results show a shift between baseline (buffer flow only) and bound analyte after the second buffer (bound analyte, following removal of non-tightly bound components).
Regarding flow rates, Grego teach controlled flow rates (slow rates) (para [0085]). Grego et al. also teach samples that are fluid sample, including biological fluid samples (para [0035], blood, serum, plasma).
Ruiz Del Agua teaches a concentration of a circulating biological drug, together with, optionally, a concentration of antibodies to the biological drug in a blood sample from a patient suffering from rheumatoid arthritis and being treated with the biological drug is associated with the patient’s response to the treatment with the biological drug (para 20). Ruiz Del Agua teaches this information would allow physicians to follow more closely their patients’ response to treatment and make informed decisions over treatment (para 21).
Ruiz Del Agua teaches a method comprising determining the concentration of a circulating biological drug in a sample from a patient treated with an administration of the biological drug (para 22-23, 44-45). The step of determining is performed at a time t1, corresponding to a time point within the period of time between two successive administrations of the biological drug, for example, day 13 after the day of the prior administration (para 22-23, 34-35). The biological drug may be infliximab, adalimumab, or golimumab (par. 14, 22, 26, 30, 32, 44). Ruiz Del Agua teaches a first capture probe to which the biological drug selectively binds and a second capture probe that selectively binds to the biological drug (e.g., TNF-alpha and antibody to said biological drug, par. 73-74).
Ruiz Del Agua teaches the method comprising: providing a biological sample obtained from a subject previously treated with a therapeutic biologic (para 13-14, 18, 22-23, 34-35); contacting the biological sample to a sensor comprising a first capture probe, wherein the first capture probe is configured to bind to the therapeutic biologic in the biological sample (e.g., TNF-alpha, para 38, 73-74); contacting the therapeutic biologic bound to the first capture probe with a second capture probe, wherein the second capture probe is configured to selectively bind to the therapeutic biologic in the biological sample (e.g., antibody to said biological drug, para 73-74); and measuring a change, wherein detection of a change is an indication of presence of the therapeutic biologic in the biological sample (e.g., par. 38, 73-74).
It would have been prima facie obvious to one having ordinary skill in the art to have modified the method of ‘165 with Bailey et al., in order to performed a first step of determining a baseline for the optical sensor comprising flowing a first buffer for a predetermined time and rate, prior to the step of contacting the sample, and further a step of performing a second baseline comprising flowing a second buffer over the first capture probe and optical sensor for a second predetermined rate and time, detecting an observation of signal shift between the first and second baseline. Regarding flowing the first buffer, one having ordinary skill would have been motivated to perform such steps (flowing first and second buffer in that indicated order) in order to remove lightly or poorly bound components. In particular, regarding optical waveguide based sensors, based both on Bailey, as well as Grego et al., performing a first baseline specifically in order to obtain/establish a reference signal, and further in order to account for instrumental drifts. One having ordinary skill would have a reasonable expectation of success because Bailey (for example as cited above) demonstrate measuring real time signal, first flowing buffer to establish a baseline/reference signal without observing binding.
Further, it would have been prima facie obvious to have performed a second baseline (flowing a second buffer following the step of contact with sample), one motivated to this additional step with second buffer in order to remove any lightly bound components at the sensor in order to obtain accurate quantitative measure (as in Grego). One having ordinary skill would have a reasonable expectation of success because Grego, like ‘165 and Bailey, is relying on methods comprising measuring using optical waveguide sensor systems, Grego specifically indicating
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of ‘165 and the cited prior art such that a biological sample from a subject previously treated with a therapeutic biologic is provided and the first and second capture probes are configured to selectively bind to the therapeutic biologic in the biological sample in order to detect the therapeutic biologic as the analyte of interest, as in Ruiz Del Agua, because detecting the therapeutic biologic would allow physicians to follow more closely their patients’ response to treatment with the therapeutic biologic and make informed decisions over treatment. One having ordinary skill in the art would have a reasonable expectation of success in combining the prior art references because Bailey teaches a method of detecting an analyte in a biological sample from a subject, such as an antibody and is generic to the specific analytes, Grego further teaching examples of analytes including analyte that is drug, and Ruiz Del Agua teaches detecting an antibody biological drug in a biological sample from a subject and is generic to the method of detection.
Regarding claim 39, ‘165 in view of the cited prior art, as detailed above, teaches the subject was administered the therapeutic biologic more than seven days before the sample was provided (concentration of the circulating biological drug in a sample from the patient is determined at a time t1, e.g., day 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 after the day of the prior administration, Ruiz Del Agua, para 35).
Regarding claims 40-41, ‘165 in view of the cited prior art teaches detecting no change or no substantial change in one or more resonance lengths at the optical sensor is an indication of absence of the therapeutic biologic in the biological sample, and is therefore considered an indication of a lack of bioavailability of the therapeutic biologic for the subject. ‘165 in view of the cited prior art teaches the detection of the change in one or more resonance wavelengths at the optical sensor is an indication of presence of the therapeutic biologic in the biological sample, and is therefore considered an indication of bioavailability of the therapeutic biologic for the subject (providing plurality of antibodies that specifically bind to the complexes or analyte, wherein binding between the antibodies and the complexes or the analyte, when the analyte is bound to the capture probes, shifts a resonant wavelength of the optical sensor; providing a plurality of particles attached to the antibodies or particles capable of binding the antibodies, wherein the particles amplify the shift of the resonant wavelength; and determining the concentration of the analyte of interest in the sample based on the shift of the resonant wavelength resulting from multiple bound particles at the ring resonator, claim 19).
Regarding claims 41 and 42, see further Bailey at para [0299] the second antibodies in a buffer, as such the combination of the cited art addresses “third buffer” as claimed, the third buffer comprising the second capture probe that is flowed over the optical sensor with captured therapeutic biologic (see as cited previously above, Bailey teaching flowing a second capture probe). The combination of the cited art above is addressing determining presence or absence of antibody against the therapeutic bound at the sensor surface (see the capture antibody immobilized at the sensor surface and the also the second antibody probe that binds the captured target that is captured by the first antibody).
Regarding claim 43, ‘165 in view of the cited prior art, as detailed above, teaches the therapeutic biologic is infliximab, adalimumab, or golimumab (Ruiz Del Agua, para 14, 22, 26, 30, 32, 44).
Regarding claim 44, ‘165 in view of the cited prior art, as detailed above, teaches the first capture probe comprises TNFα (Ruiz Del Agua, e.g., par. 73-74).
Regarding claim 45, ‘165 in view of the cited prior art teaches the second capture probe comprises an anti-human IgG antibody (Ruiz Del Agua, para 74, 51).
Regarding claim 46, ‘165 in view of the cited prior art teaches the biological sample comprises serum (Ruiz Del Agua, para 18, 37).
Regarding claim 47, ‘165 in view of the cited prior art teaches the subject is human (e.g., Ruiz Del Agua, para 17-18).
Regarding claim 48, ‘165 in view of the cited prior art, as detailed above, teaches the first capture probe comprises TNFα (Ruiz Del Agua, e.g., para 73-74), the therapeutic biologic comprises infliximab or adalimumab (Ruiz Del Agua, para 14, 22, 26, 30, 32, 44), and the second capture probe comprises an anti-human IgG antibody (Ruiz Del Agua, para 74, 51).
Claim 49 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-21 of U.S. Patent No. 9,921,165 (‘165) in view of Bailey et al., Grego et al., and Ruiz Del Agua, as applied to claim 38 above, and further in view of Kaempfer et al.
Regarding claim 49, Bailey teaches the surface density of the capture probes on the surface can be varied to tune the dynamic range of analyte detection and that the surface of an optical sensor can have a range of capture probes spanning from a single capture probe to a number of capture probes that fully saturates all the available binding sites on the surface (para 197, 199), but fails to specifically teach the amount of the first capture probe attached to the optical sensor is from 10 µg to 300 µg.
As another example of a resonance device sensing surface comprising ligand subject to binding, see Kaempfer et al. at for example col. 18, lines 39-65, col. 19, lines 12-15, 37-45, col. 20, lines 22-27, teaching an amount of immobilized ligand for binding/detection that is 100 µg (immobilized sCD28, other examples immobilized sB7-2 on Biacore sensing device).
Although Bailey fails to specifically teach the amount of the first capture probe attached to the optical sensor is from 10 µg to 300 µg, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value for a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation”. Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. at 458, 105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
In the instant case, the prior art teaches that the surface density of the capture probes on the surface can be varied to tune the dynamic range of analyte detection and that the surface of an optical sensor can have a range of capture probes spanning from a single capture probe to a number of capture probes that fully saturates all the available binding sites on the surface (Bailey, para 197, 199). Further, see Kaempfer as an example in the art showing 100µg as an appropriate surface amount of a ligand/binding agent at a sensing surface/chip device.
Absent unexpected results, it would have been prima facie obvious for one of ordinary skill in the art to have arrived at the claimed amount of the first capture probe attached to the optical sensor of from 10 µg to 300 µg by routine optimization, namely by optimizing/selecting values starting with the amount as disclosed by Kaempfer, shown as a an appropriate coating amount, (100 µg, notably a value that falls within the claimed range) in order to uncover the optimum workable ranges of the surface density and amount of the capture probes on the surface of the optical sensor. One having ordinary skill in the art would have a reasonable expectation of success in arriving at the claimed amount of the first capture probe attached to the optical sensor through routine optimization because the prior art discloses varying surface density and amount of the capture probes on the surface specifically for the purpose of tuning the dynamic range of analyte detection and because Kaempfer, by showing immobilization of 100 µg, supports this amount as an appropriate, workable amount.
Claims 50-54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-21 of U.S. Patent No. 9,921,165 (‘165) in view of Bailey et al., Grego et al., and Ruiz Del Agua, as applied to claim 38 above, and further in view of Cho et al., Miao et al., Abrams et al., and Barrett et al.
Regarding claim 50, ‘165 in view of Bailey, Grego et al. and Ruiz Del Agua teaches contacting a first capture probe attached to an optical sensor with the biological sample comprises flowing the biological sample over the optical sensor (Bailey, para 100, 107). Bailey exemplifies flowing solutions at various flow rates for various amounts of time for binding events (e.g., para 303, 305, 324, e.g., functionalization and detection steps, 5µL/min, additional steps 30 µL/min, other binding steps 30 µL/min, also teaching times of about 35 minutes, about 30 minutes).
‘165 in view of Bailey, Grego et al. and Ruiz Del Agua fails to specifically teach flowing the biological sample over the optical sensor for a period of time of 3 minutes at a rate of flow of 40 µl/min.
However, notably Grego teaches a method of sensing analytes using an optical sensor, including flowing solution over a sensor surface (e.g., abstract, para 16, 72). Grego teaches controlling the flow rate to allow for taking of optical readings (e.g., para 85).
Although the claims of ‘165 are silent as to the duration and flow rate, and that of Bailey differ (generally longer durations and slightly different flow rates), see further as examples of optical sensing/flow through binding systems, each of Cho et al., para [0671] teaching flowing sample of binding surface at a flow rate of 50 µl/min for 4-5 min to allow association/binding (Biacore flow through chip/system), Miao et al., para [0607] injecting sample of a surface for association/binding at a rate of 40 µl/min for 4-5 minutes (Biacore flow through chip/system), Abrams et al., para [0440] injecting over a binding surface at a rate of 40µl/min for 4 minutes, and Barrett et al., para [0269], injecting over a binding surface at a rate of 40 µl/min for 10 minutes (SPR flow through chip device/system).
Although Bailey in view of Grego and Ruiz Del Agua fails to specifically teach flowing the biological sample over the optical sensor for a period of time of 3 minutes at a rate of flow of 40 µl/min, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value for a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation”. Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. at 458, 105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
The prior art supports that both contact time and rate is a result effective variable, namely a variable optimizable in order to achieve binding/association between capture ligand and analyte flowed through a chip/device. See as cited above, flow rate may be varied/controlled to allow for reaction or incubation time (Grego, par. 85).
The claims of ‘165 are silent as to flow rate/duration, and although Bailey teaches a different flow rate/duration than presently claimed, see further Cho, Maio, Abrams and Barrett, these references teach the same or extremely similar flow rate and duration (flow rates of each for achieving binding are taught as 40µl/min, with durations from 3-5 minutes). Based on these references, and absent unexpected results, it would have been prima facie obvious for one of ordinary skill in the art to have arrived at the claimed time and rate for flowing the biological sample over the optical sensor of a period of time of 3 minutes at a rate of flow of 40 µl/min by routine optimization, namely by optimizing within the art disclosed ranges appropriate for achieving binding/association at a sensor capture surface in a flow through device/system, in order to uncover the optimum workable ranges of the contact time and flow rate. One having ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed time and rate for flowing the sample over the optical sensor through routine optimization because the prior art discloses varying the contact time with assay parameters such as binding kinetics and to limit non-specific binding and varying the flow rates for the purpose of allow for reaction or incubation time, and because these various references in the prior art support that such a flow rate and time was known in the art as appropriate for achieving binding/association. It would have been well within the skill level of the ordinary artisan to optimize by selecting within these known art recognized ranges, known suitable for achieving binding.
Regarding claims 51-54, ‘165, Bailey in view of the cited prior art teaches contacting the therapeutic biologic bound to the first capture probe with a second capture probe comprises flowing a buffer comprising the second capture probe over the attached therapeutic biologic (e.g., antibody in buffer such as PBS, Bailey, par. 282, 299). Bailey exemplifies flowing solutions at various flow rates for various amounts of time (e.g., par. 281, 282, 305). Bailey in view of the cited art (Grego and Ruiz Del Agua) fails to specifically teach the specifically claimed durations and flow rates for the steps as recited at claims 51-54.
However, for the same reasons as discussed above, it would have been prima facie obvious to have arrived at the claimed durations and flow rates out of routine optimization of experimental conditions, namely by testing values similar to those disclosed by the prior art as discussed in detail above, recognized suitable for the purpose of achieving binding/association to uncover the optimum workable conditions. The prior art supports that it is well within the skill of the ordinary artisan to perform routine experimentation and uncover the optimum workable conditions in terms of duration and flow rate.
Copending 17/220,888
Claims 38-39 and 41-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 79-80, 82, 84-97, 99-111, 113-115,117 and 118 of copending Application No. 17/220,888 in view of Bailey et al., Grego et al. and Ruiz Del Agua.
Regarding claim 38, ‘888 teaches a method (claim 79) comprising:
(a) providing a biological sample from a subject comprising a plurality of immunoglobulins (contacting a biological sample from a subject comprising a plurality of immunoglobulins, claim 79);
(b) contacting the biological sample to an optical sensor comprising a first capture probe, wherein the first capture probe is configured to selectively bind to the immunoglobulins in the biological sample (contacting a biological sample a subject comprising a plurality of immunoglobulins with a plurality of optical ring resonators under conditions that permit the immunoglobulins to bind to a plurality of antigens, such that the plurality of optical ring resonators comprises a plurality of antigens, claim 79);
(c) contacting the immunoglobulins bound to the first capture probe with a second capture probe, wherein the second capture probe is configured to selectively bind to the immunoglobulins in the biological sample (contacting one or more probes specific to one or more immunoglobulin types with the immunoglobulins bound to the plurality of antigens on the optical ring resonators, claim 79); and
(d) measuring a change in in one or more resonance wavelengths of the optical sensor, wherein detection of a change in the one or more resonance wavelengths is an indication of presence of the immunoglobulins in the biological sample in one or more resonance wavelengths at the optical sensor, (detecting changes in resonance wavelength, claims 79-80).
‘888 teaches the analyte is immunoglobulins (claim 79), but fails to teach the immunoglobulins are a therapeutic biologic and that the biological sample is obtained from a subject previously treated with the therapeutic biologic.
Bailey is as cited in detail previously above teaching a method substantially similar to that of ‘888 (methods performing detection by flowing buffer/sample through a similar assay device/system), Bailey teaches the analyte of interest may be a polypeptide, protein, or antibody (paras 34, 152). Bailey teaches the sample may be a biological material obtained from an organism, such as a sample from a patient (paras 158, 252; i.e., biological sample).
Although Bailey does not clearly state determining a first baseline resonance wavelength for an optical sensor wherein the first baseline comprises flowing a buffer over the optical sensor at a first predetermined time and rate, see Bailey at for example Figure 23, the spectrum shows flowing through a buffer only from time 0 to about 7500 seconds. Figure 23 shows real time sensor response (para [0312]).
Grego et al. is also as cited previously above, Grego teach a method of determining an analyte (such as, for example, a drug) in a subject’s sample using an optical sensor (abstract, paras, [0016] [0034] and [0072]). See para [0039], Grego teach performing an initial baseline measurement as a reference optical measurement signal. See also para [0071], Grego describe establishing a baseline to account for tests and to correct for instrumental shift. The method of Grego comprises providing a biological sample obtained from the subject, determining a first baseline resonance wavelength for an optical signal by flowing a first buffer over the sensor at a first predetermined rate for a first predetermined time (see para [0072], t0 to t1 only a reference solution is flowed through fluidic structure, producing flat signal), contacting sample to the optical sensor, the sensor comprising first capture probe that selectively binds the analyte in the sample (para [0072], flowing sample fluid through structure from t1 to t2, target analytes become bound to analyte-specific receptors of the sensors), determining a second baseline resonance wavelength for the optical sensor by flowing second buffer over the first capture probe and the optical sensor for a second predetermined period of time and for a second predetermined rate (para [0072], at t2 flow of fluid sample replaced with another flow of buffer solution, see reference at para [0072] to detector readings taken from t2-t3, observing signal that reflects slight reduction in concentrations as some non-tightly bound components are removed by the buffer). See at para [0072], Grego report detecting observation of a signal indicating a shift from the first t the second baseline, Grego determining availability of analyte in the sample upon detection of signal (quantitative measure of target analyte mass or concentration provided).
Grego’s example at para [0072] teaches that second step of flowing buffer as a step that removes non-tightly bound components. Grego observes a shift from the first buffer (flat signal) to a second signal representing binding event, and further a slight reduction in signal representing removal of the non-tightly bound components. Overall, Grego’s results show a shift between baseline (buffer flow only) and bound analyte after the second buffer (bound analyte, following removal of non-tightly bound components).
Regarding flow rates, Grego teach controlled flow rates (slow rates) (para [0085]). Grego et al. also teach samples that are fluid sample, including biological fluid samples (para [0035], blood, serum, plasma).
Ruiz Del Agua teaches a concentration of a circulating biological drug, together with, optionally, a concentration of antibodies to the biological drug in a blood sample from a patient suffering from rheumatoid arthritis and being treated with the biological drug is associated with the patient’s response to the treatment with the biological drug (para 20). Ruiz Del Agua teaches this information would allow physicians to follow more closely their patients’ response to treatment and make informed decisions over treatment (para 21).
Ruiz Del Agua teaches a method comprising determining the concentration of a circulating biological drug in a sample from a patient treated with an administration of the biological drug (para 22-23, 44-45). The step of determining is performed at a time t1, corresponding to a time point within the period of time between two successive administrations of the biological drug, for example, day 13 after the day of the prior administration (para 22-23, 34-35). The biological drug may be infliximab, adalimumab, or golimumab (par. 14, 22, 26, 30, 32, 44). Ruiz Del Agua teaches a first capture probe to which the biological drug selectively binds and a second capture probe that selectively binds to the biological drug (e.g., TNF-alpha and antibody to said biological drug, par. 73-74).
Ruiz Del Agua teaches the method comprising: providing a biological sample obtained from a subject previously treated with a therapeutic biologic (para 13-14, 18, 22-23, 34-35); contacting the biological sample to a sensor comprising a first capture probe, wherein the first capture probe is configured to bind to the therapeutic biologic in the biological sample (e.g., TNF-alpha, para 38, 73-74); contacting the therapeutic biologic bound to the first capture probe with a second capture probe, wherein the second capture probe is configured to selectively bind to the therapeutic biologic in the biological sample (e.g., antibody to said biological drug, para 73-74); and measuring a change, wherein detection of a change is an indication of presence of the therapeutic biologic in the biological sample (e.g., par. 38, 73-74).
It would have been prima facie obvious to one having ordinary skill in the art to have modified the method of ‘888 with Bailey et al. and Grego et al., in order to performed a first step of determining a baseline for the optical sensor comprising flowing a first buffer for a predetermined time and rate, prior to the step of contacting the sample, and further a step of performing a second baseline comprising flowing a second buffer over the first capture probe and optical sensor for a second predetermined rate and time, detecting an observation of signal shift between the first and second baseline. Regarding flowing the first buffer, one having ordinary skill would have been motivated to perform such steps (flowing first and second buffer in that indicated order) in order to remove lightly or poorly bound components. In particular, regarding optical waveguide based sensors, based both on Bailey, as well as Grego et al., performing a first baseline specifically in order to obtain/establish a reference signal, and further in order to account for instrumental drifts. One having ordinary skill would have a reasonable expectation of success because Bailey (for example as cited above) demonstrate measuring real time signal, first flowing buffer to establish a baseline/reference signal without observing binding.
Further, it would have been obvious to have performed a second baseline (flowing a second buffer following the step of contact with sample), one motivated to this additional step with second buffer in order to remove any lightly bound components at the sensor in order to obtain accurate quantitative measure (as in Grego). One having ordinary skill would have a reasonable expectation of success because Grego, like ‘888 and Bailey, is relying on methods comprising measuring using optical waveguide sensor systems, Grego specifically indicating
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of ‘888 and the cited prior art such that a biological sample from a subject previously treated with a therapeutic biologic is provided and the first and second capture probes are configured to selectively bind to the therapeutic biologic in the biological sample in order to detect the therapeutic biologic as the analyte of interest, as in Ruiz Del Agua, because detecting the therapeutic biologic would allow physicians to follow more closely their patients’ response to treatment with the therapeutic biologic and make informed decisions over treatment. One having ordinary skill in the art would have a reasonable expectation of success in combining the prior art references because Bailey teaches a method of detecting an analyte in a biological sample from a subject, such as an antibody and is generic to the specific analytes, Grego further teaching examples of analytes including analyte that is drug, and Ruiz Del Agua teaches detecting an antibody biological drug in a biological sample from a subject and is generic to the method of detection.
Regarding claim 39, ‘888 in view of the cited prior art, as detailed above, teaches the subject was administered the therapeutic biologic more than seven days before the sample was provided (concentration of the circulating biological drug in a sample from the patient is determined at a time t1, e.g., day 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 after the day of the prior administration, Ruiz Del Agua, para 35).
Regarding claims 41 and 42, see further Bailey at para [0299] the second antibodies in a buffer, as such the combination of the cited art addresses “third buffer” as claimed, the third buffer comprising the second capture probe that is flowed over the optical sensor with captured therapeutic biologic (see as cited previously above, Bailey teaching flowing a second capture probe). The combination of ‘888 and the cited art above is addressing determining presence or absence of antibody against the therapeutic bound at the sensor surface (see the capture antibody immobilized at the sensor surface and the also the second antibody probe that binds the captured target that is captured by the first antibody).
Regarding claim 43, ‘888 in view of the cited prior art, as detailed above, teaches the therapeutic biologic is infliximab, adalimumab, or golimumab (Ruiz Del Agua, para 14, 22, 26, 30, 32, 44).
Regarding claim 44, ‘888 in view of the cited prior art, as detailed above, teaches the first capture probe comprises TNFα (Ruiz Del Agua, e.g., par. 73-74).
Regarding claim 45, ‘888 in view of the cited prior art teaches the second capture probe comprises an anti-human IgG antibody (Ruiz Del Agua, para 74, 51).
Regarding claim 46, ‘888 in view of the cited prior art teaches the biological sample comprises serum (copending claim 102).
Regarding claim 47, ‘888 in view of the cited prior art teaches the subject is human (e.g., Ruiz Del Agua, para 17-18).
Regarding claim 48, ‘888 in view of the cited prior art, as detailed above, teaches the first capture probe comprises TNFα (Ruiz Del Agua, e.g., para 73-74), the therapeutic biologic comprises infliximab or adalimumab (Ruiz Del Agua, para 14, 22, 26, 30, 32, 44), and the second capture probe comprises an anti-human IgG antibody (Ruiz Del Agua, para 74, 51).
Claim 49 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 79-80, 82, 84-97, 99-111, 113-115,117 and 118 of copending Application No. 17/220,888 in view of Bailey et al., Grego et al. and Ruiz Del Agua, as applied to claim 38 above, and further in view of Kaempfer et al.
Regarding claim 49, ‘888 and Bailey (and the cited art) teaches the surface density of the capture probes on the surface can be varied to tune the dynamic range of analyte detection and that the surface of an optical sensor can have a range of capture probes spanning from a single capture probe to a number of capture probes that fully saturates all the available binding sites on the surface (para 197, 199), but fails to specifically teach the amount of the first capture probe attached to the optical sensor is from 10 µg to 300 µg.
As another example of a resonance device sensing surface comprising ligand subject to binding, see Kaempfer et al. at for example col. 18, lines 39-65, col. 19, lines 12-15, 37-45, col. 20, lines 22-27, teaching an amount of immobilized ligand for binding/detection that is 100 µg (immobilized sCD28, other examples immobilized sB7-2 on Biacore sensing device).
Although ‘888 and the cited art (including Bailey) fails to specifically teach the amount of the first capture probe attached to the optical sensor is from 10 µg to 300 µg, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value for a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation”. Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. at 458, 105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
In the instant case, the prior art teaches that the surface density of the capture probes on the surface can be varied to tune the dynamic range of analyte detection and that the surface of an optical sensor can have a range of capture probes spanning from a single capture probe to a number of capture probes that fully saturates all the available binding sites on the surface (Bailey, para 197, 199). Further, see Kaempfer as an example in the art showing 100µg as an appropriate surface amount of a ligand/binding agent at a sensing surface/chip device.
Absent unexpected results, it would have been prima facie obvious for one of ordinary skill in the art to have arrived at the claimed amount of the first capture probe attached to the optical sensor of from 10 µg to 300 µg by routine optimization, namely by optimizing/selecting values starting with the amount as disclosed by Kaempfer, shown as a an appropriate coating amount, (100 µg, notably a value that falls within the claimed range) in order to uncover the optimum workable ranges of the surface density and amount of the capture probes on the surface of the optical sensor. One having ordinary skill in the art would have a reasonable expectation of success in arriving at the claimed amount of the first capture probe attached to the optical sensor through routine optimization because the prior art discloses varying surface density and amount of the capture probes on the surface specifically for the purpose of tuning the dynamic range of analyte detection and because Kaempfer, by showing immobilization of 100 µg, supports this amount as an appropriate, workable amount.
Claims 50-54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 79-80, 82, 84-97, 99-111, 113-115, 117 and 118 of copending Application No. 17/220,888 in view of Bailey et al., Grego et al. and Ruiz Del Agua, as applied to claim 38 above, and further in view of Cho et al., Miao et al., Abrams et al., and Barrett et al.
Regarding claim 50, ‘888 in view of Bailey, Grego et al. and Ruiz Del Agua teaches contacting a first capture probe attached to an optical sensor with the biological sample comprises flowing the biological sample over the optical sensor (Bailey, para 100, 107). Bailey exemplifies flowing solutions at various flow rates for various amounts of time for binding events (e.g., para 303, 305, 324, e.g., functionalization and detection steps, 5µL/min, additional steps 30 µL/min, other binding steps 30 µL/min, also teaching times of about 35 minutes, about 30 minutes).
‘888 in view of Bailey, Grego et al. and Ruiz Del Agua fails to specifically teach flowing the biological sample over the optical sensor for a period of time of 3 minutes at a rate of flow of 40 µl/min.
However, notably Grego teaches a method of sensing analytes using an optical sensor, including flowing solution over a sensor surface (e.g., abstract, para 16, 72). Grego teaches controlling the flow rate to allow for taking of optical readings (e.g., para 85).
Although the duration and flow rate of Bailey differ (generally longer durations and slightly different flow rates), see further as examples of optical sensing/flow through binding systems, each of Cho et al., para [0671] teaching flowing sample of binding surface at a flow rate of 50 µl/min for 4-5 min to allow association/binding (Biacore flow through chip/system), Miao et al., para [0607] injecting sample of a surface for association/binding at a rate of 40 µl/min for 4-5 minutes (Biacore flow through chip/system), Abrams et al., para [0440] injecting over a binding surface at a rate of 40µl/min for 4 minutes, and Barrett et al., para [0269], injecting over a binding surface at a rate of 40 µl/min for 10 minutes (SPR flow through chip device/system).
Although ‘888 in view of the cited prior art fails to specifically teach flowing the biological sample over the optical sensor for a period of time of 3 minutes at a rate of flow of 40 µl/min, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value for a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation”. Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. at 458, 105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
The prior art supports that both contact time and rate is a result effective variable, namely a variable optimizable in order to achieve binding/association between capture ligand and analyte flowed through a chip/device. See as cited above, flow rate may be varied/controlled to allow for reaction or incubation time (Grego, par. 85).
The claims of ‘888 are silent as to flow rate/duration, and although Bailey teaches a different flow rate/duration than presently claimed, see further Cho, Maio, Abrams and Barrett, these references teach the same or extremely similar flow rate and duration (flow rates of each for achieving binding are taught as 40µl/min, with durations from 3-5 minutes). Based on these references, and absent unexpected results, it would have been prima facie obvious for one of ordinary skill in the art to have arrived at the claimed time and rate for flowing the biological sample over the optical sensor of a period of time of 3 minutes at a rate of flow of 40 µl/min by routine optimization, namely by optimizing within the art disclosed ranges appropriate for achieving binding/association at a sensor capture surface in a flow through device/system, in order to uncover the optimum workable ranges of the contact time and flow rate. One having ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed time and rate for flowing the sample over the optical sensor through routine optimization because the prior art discloses varying the contact time with assay parameters such as binding kinetics and to limit non-specific binding and varying the flow rates for the purpose of allow for reaction or incubation time, and because these various references in the prior art support that such a flow rate and time was known in the art as appropriate for achieving binding/association. It would have been well within the skill level of the ordinary artisan to optimize by selecting within these known art recognized ranges, known suitable for achieving binding.
Regarding claims 51-54, ‘888, and Bailey in view of the cited prior art teaches contacting the therapeutic biologic bound to the first capture probe with a second capture probe comprises flowing a buffer comprising the second capture probe over the attached therapeutic biologic (e.g., antibody in buffer such as PBS, Bailey, par. 282, 299). Bailey exemplifies flowing solutions at various flow rates for various amounts of time (e.g., par. 281, 282, 305). Bailey in view of the cited art (Grego and Ruiz Del Agua) fails to specifically teach the specifically claimed durations and flow rates for the steps as recited at claims 51-54.
However, for the same reasons as discussed above, it would have been prima facie obvious to have arrived at the claimed durations and flow rates out of routine optimization of experimental conditions, namely by testing values similar to those disclosed by the prior art as discussed in detail above, recognized suitable for the purpose of achieving binding/association to uncover the optimum workable conditions. The prior art supports that it is well within the skill of the ordinary artisan to perform routine experimentation and uncover the optimum workable conditions in terms of duration and flow rate.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 06/04/2025 have been fully considered but they are not persuasive for the following reasons.
Regarding remarks page 7 specific to the previous rejection of claims under 35 U.S.C. 112(b), see as indicated above, the previous rejection of claims is withdrawn in response to Applicant’s amendments to the claims.
Regarding the rejection of claims under 35 U.S.C. 103 (remarks pages 7-9, including remarks specific to dependent claims 50-54), Applicant refers to the amendments to the claims (specifically at steps b-g). See the amended grounds of rejection set forth in detail above in response to the amendments to the claims.
Regarding the rejections of claims on the grounds of non-statutory double patenting (remarks pages 9-10), Applicant refers the remarks specific to the art applied previously and the amended claims. See as discussed above, the rejections are not withdrawn in light of the amended grounds of rejection set forth in response to the amended claims.
Correspondence
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/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677