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.
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.
Claims 1-25 are rejected under 35 U.S.C. 103 as being unpatentable over Wasson (US 2021/0052882) in view of Stewart (US 2016/0166310).
Regarding claims 1-5, 8 and 20, Wasson discloses an electroporation system including an instrument with at least one energy delivery body ([0120]), which can include a monopolar configuration using a dispersive return electrode ([0065], [0119]), connected to a generator operated with an “algorithm” (i.e. whatever control processes produce the desired outcome) that results in outputting biphasic pulsed electric fields (fig. 1B) to create a plurality of zones in a bulls-eye arrangement, including at least a pulsed electric field zone and a thermal zone (e.g. fig. 13, [0137]), which will result in, among other things, an increase in an adaptive immune response which can be considered to create “an immune response zone” ([0138]). Wasson further discloses that “inter-cycle delays” and “inter-packet” delays are used to control zone size ([0048]). More generally, since the zone does not exist without the electrical parameters of the waveform, all electrical parameters can be considered “configured to control the size of the pulsed electric field/thermal zone.” Wasson further discloses that the generator is capable of outputting a significant range of values including voltages up to 10kV ([0122], note specifically a 1.2-5kV range for H-FIRE in [0138], and values “over” 600 V/cm for IRE in [0007]) at frequencies up to 100 MHz ([0060]) which includes the fundamental frequency given the other pulse parameters disclosed (e.g. no delay between the pulses is taught, [0046]). Wasson teaches the switch time can be 0.1 microseconds ([0059]) which is not less than 0.1 microseconds. However, shorter switch times are commonly known among electroporation generators, and Wasson teaches that while one type of electroporation may be particularly useful in some situations (“H-FIRE,” e.g. [0023]), Wasson also teaches that many other types of electroporation are contemplated and possible for the disclosed generator, including to elicit an immune response (“IRE, H-FIRE, RE or ECT,” [0018]). See also paragraphs [0034], [0098] and [0106] which is of particular note because it discloses two different types of electroporation in the same procedure, along with [0161]. Stewart, for example, discloses an electroporation generator and teaches that a switch time can range from zero to hundreds of microseconds ([0032]), thus overlapping with Wasson’s range. It has been held that the combination of known elements according to known methods to yield predictable results is an obvious modification (MPEP 2141(III)), where in this case the known elements are the elements necessary to allow an electroporation generator to produce specific waveform parameters. Therefore, before the application was filed, it would have been obvious to one of ordinary skill in the art to modify the electroporation generator of Wasson to include the ability to output any commonly known parameters useful for electroporation, including a less than 0.1 microsecond switch time as taught by Stewart, that would produce the predictable result of allowing a user to choose electrical parameters for interacting with issue in a desired manner. Further, it would have been obvious to one of ordinary skill in the art, before the application was filed, to modify the system of Wasson to use any of the electrode configurations disclosed by Wasson, including the use of a dispersive ground pad thus defining monopolar ablation, to produce the predictable result of treating tissue in a desired manner.
Regarding claims 6, 7 and 9, Wasson does not disclose the specific inter-cycle delays and inter-pulse delays, although it is noted these delays are not defined with respect to anything other than themselves. Wasson does teach that the inter-cycle and inter-pulse delays are used to control the size of the various zones ([0048]), where the delay between one of the pulses and the bursts are understood to be one of the “inter-cycle delay” and the “inter-pulse” delay since terms like cycle, burst, pulse, dose and train are used interchangeably to describe various elements of pulsed electric waveforms within the art. For these delays, Wasson teaches a duration of a large range of values including specifically 10 microseconds and 3 seconds ([0063]). Therefore, before the application was filed, it would have been obvious to one of ordinary skill in the art to modify the system of Wasson to use any commonly known inter-cycle delays and inter-pulse delays including on the order of microseconds and seconds as taught by Wasson that would produce the predictable result of controlling the size of the zones created by the procedure to produce the result desired by an operator. It is noted that the 10-microsecond delay will at least “inhibit” cavitation relative to some unclaimed, undefined hypothetical alternative inter-cycle delay.
Regarding claims 10 and 21-25, Wasson does not specifically disclose that the treatment procedure involves, variously, a dose of 5-6 minutes, where a dose comprises 100 packets with 3 seconds between the packets, where a packet has 40 biphasic pulses with 100 microseconds between the pulses. However, these variables are all well within the parameters commonly used in the art for pulsed electric field treatment. Wasson discloses the three tiers of treatment: the dose being the total duration of treatment, the packet being the burst ([0059]) and the pulse being the pulse ([0062]). Wasson further discloses that the number of bursts and pulses within bursts can be from 1-5000 ([0062]). Wasson further discloses that the delay between the pulses and bursts can be between microseconds and seconds ([0063]). Further, Wasson specifically discloses 100 microseconds of on-time for the packets (fig. 1B). Finally, Wasson discloses that the pulses can be chosen to create cell death on the order of “minutes” ([0053]) which is understood to be a dose range that includes single digit minutes. Therefore, before the application was filed, it would have been obvious to modify the system of Wasson to use any of the values disclosed for the pulsed electric field by Wasson, including a dose of 5-6 minutes, 100 packets in a dose, 3 seconds between packets and 40 pulses a packet, 1000 microseconds between pulses, 100 microseconds on-time for the packets, or any other ranges of those values disclosed by Wasson, that would produce the predictable result of ablating tissue while promoting an immune response as taught by Wasson.
Regarding claims 11-16, the various mechanisms of immune response are understood to be related in the presence of pulsed electric fields such that even a small amount of those responses are understood to be a necessary product of the type of pulsed electric field which results in the improved immune response disclosed by Wasson. This is the broadest reasonable interpretation of the claims that does not result in an indefiniteness rejection and potentially an enablement rejection. The specification does not describe what specific “algorithm” would produce these results independently, and it is not clear what specific values in the massive parameter ranges provided in the specification are necessary to produce these specific results. For example, the CD8+/CD4+ T-cell ratio appears in exactly one part of the specification ([00246]-[00249]) as a result of every treatment performed in a trial for which there appears to be no specific pulsed field parameters provided. If Applicant’s have invented a specific system that is capable of producing these results independently, and/or if there are specific parameters necessary to produce these specific results, the claims should reflect those details. It is also noted that the fact that these are apparatus claims and not method claims will complicate efforts to claim steps and not structure as apparatus claims are directed to what an invention is, not what it does (MPEP 2114). As long as the prior art is capable of producing the results (by, for example, disclosing certain operational parameters), it will read on the claimed structure that is merely capable of producing that result. In the interest of compact prosecution, a list of references which are relevant to the various immune responses have been provided in the conclusion below.
Regarding claims 17-19, the claims do not require the use of an immune checkpoint inhibitor, only that the system might produce some result if it so happened to be used with an immune checkpoint inhibitor. Being a functional limitation, the system of Wasson reads on the claims because there is some combination of parameters disclosed by Wasson that would produce the claimed result if used in some hypothetical combination with a hypothetical amount of an anti-PD1 therapy. However, in the interest of compact prosecution, see the references related to PD-L1 use in the previous Action. Like claims 11-16, these claims must either be interpreted extremely broadly or as indefinite and potentially lacking enablement.
Response to Arguments
Applicant's arguments filed 08 May 2006 have been fully considered but, to the degree they are relevant to the updated rejections, they are not persuasive. Applicant’s arguments regarding claim 1 center on the fact that Wasson is primarily directed to what is called “H-FIRE” as a specific form of electroporation. There are several issues with this line of reasoning.
First, regarding claim 1 specifically, the claim is not directed to a method of treating tissue, but a generator capable of outputting certain parameters, where these parameters are capable of producing certain results in tissue. Therefore, the issue is not whether Wasson would operate the system at any given subset of parameters, but whether the generator is capable of operating at those parameters. Out of all the various relevant prior art, Wasson was cited for an extensive discussion of significant ranges of output values that overlap with, and in some cases entirely encompass, the claimed ranges. As noted in the rejection, Wasson’s disclosure of a voltage range from 0-10kV along with frequencies from 0-100 MHz, while extremely large, are simply an indication that generators in this space are both known to be useful at those ranges and that the level of ordinary skill in the art would be familiar with the creation and operation of generators in those ranges. Also as discussed in the rejection, Wasson discloses other types of electroporation can be generated by the system, such that the generator is clearly not intended entirely and only for use in H-FIRE (even if the steps are not relevant to the pending claims).
Second, even regarding H-FIRE specifically, Applicant’s arguments regarding what H-FIRE entails are not commensurate with Wasson’s disclosure. For example, Applicant quotes Wasson as disclosing a relatively lower range of voltage in paragraph [0006] but it will be noted the units are kV/cm, not kV. Depending on the area over which the voltages are applied, higher or lower voltages may be necessary to generate the desired kV/cm. It is not surprising, therefore, that Wasson discloses a voltage range up to 10kV ([0055]), a teaching not addressed by Applicant. Further, while it may or may not be persuasive to argue that it would not be obvious to modify an H-FIRE method as specifically defined by Wasson, that would not be an argument that the rejection is improper both because the invention is directed to a generator not a method, and because Wasson explicitly teaches or suggests at least most of the claimed ranges. As for “teaching away,” Wasson cannot be understood to teach away from using parameters specifically contemplated by Wasson for any of the various types of electroporation disclosed beyond H-FIRE. As for the switch time/inter-pulse delay, while Wasson discloses some specific examples of 1 microsecond, Wasson also teaches, specifically in the context of H-FIRE, a lower value of 0.1 microsecond ([0059]). While a secondary reference is cited in the interest of compact prosecution, there is no evidence of functional difference between 0.1 microsecond and 0.0999999~ microseconds (i.e. less than 0.1 microseconds).
Regarding claims 17-19, this issue is likely to remain a point of contention. The argument in the rejections is not that the prior art discloses that the claimed steps produce the claimed results, because the claims do not describe a method. The argument in the rejection is merely that the prior art discloses the claimed generator which can produce a waveform (i.e. a waveform having the disclosed or obvious waveform parameters) that when used in conjunction with an unclaimed drug would produce the claimed results. Therefore, that is all the prior art has to show at this point. If the claims were amended to include a system with an immune checkpoint inhibitor in conjunction and the energy delivery, then a rejection using a reference like Qiao (or those cited in the Conclusion of the previous Action) may be provided. The arguments and the claims are close to creating an enablement issue under 35 U.S.C. 112(a). That is, if Applicant states that using a waveform having given parameters in the presence of a particular drug produces a specific effect, but then argues that the prior art producing a waveform having given parameters in the presence of a hypothetical/unclaimed substance does not produce that specific effect, then the question is raised as to how a person of ordinary skill in the art would know how to produce that specific effect if not according to Applicant’s instructions. To give another example, Applicant’s specification explicitly associates a 10-1000 microsecond inter-cycle delay (three orders of magnitude) with inhibiting cavitation. Claim 6 recites a delay of at least 10 microseconds, claim 7 recites the delay inhibits cavitation. If the at least 10 microsecond delay does not inhibit cavitation, claim 7 is not enabled and it would be unclear what generator element produces an inter-cycle delay that does inhibit cavitation. MPEP 2112 may be relevant, particular the fact that “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.”
Regarding claims 6, 9, 10 and 21-25, the rejection is not stating that the parameter terms are interchangeable within a given reference, but rather that various prior art documents use terms differently. Thus, the issue is not whether the prior art uses exactly the same terminology but whether the prior art is describing the same attributes of a waveform. Further, as discussed in the rejection, the prior art expressly discloses ranges for the equivalent values that overlapped with the claimed ranges. This creates grounds for obviousness on its face (MPEP 2144.05). As noted above, Wasson is specifically cited for the broad teachings about which parameters are known to be useful by a generator. It will be difficult to argue that a person of ordinary skill in the art, the level of which is indicated by references such as Wasson, would not be motivated to produce waveforms using the values disclosed by Wasson. Short of secondary considerations, it will always be argued that it is obvious to operate a generator at parameters disclosed for the generator. Finally, while not particularly germane to the rejections as written, it is noted that the variously claimed parameters are not claimed together. That is, none of claims 6, 9, 10 and 21-25 depend on each other. An argument that a very specific set of waveform parameters are necessary to produce a specific result is less persuasive when those parameters are not claimed together.
In the examiner’s experience, electroporation for tissue destruction can be a difficult technology to patent exactly because the prior art is so full of generators outputting waveforms with massive ranges of values. This not only establishes a prima facie case for obviousness of values in those ranges but establishes that the level of ordinary skill in the art is very high precisely because, as Applicant notes in the remarks, “lesion formation is extremely complex” and the presumption is that a person of ordinary skill in the art would know how to make and use the prior art (MPEP 2121). It will be difficult to persuasively argue that a person of ordinary skill in the art of electroporation would be able to make a generator that can output parameter ranges but would not be motivated to ever use values in those ranges to produce the results the generator was created to produce in the first place, regardless of whether such a person knew those parameters would produce the results disclosed by Applicant. It may be possible that a way forward is to be more specific about what exactly constitutes the “algorithm” and/or how the algorithm is generated/applied. Applicant’s paragraph [0158] (of the printed publication, US 2024/0350185), for example, notes that the algorithm is picked by the generator on the grounds of sensed information. A generator with a processor that performs some steps to select values in narrow ranges according to some specific inputs might be meaningfully different than a generator that is simply capable of outputting values in those narrow ranges so that it would be obvious to do so. There may be other differences from the prior art regarding processing steps and what the algorithm actually does/is. If Applicant would care to discuss these issues before filing a response, the examiner’s contact information can be found below.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Regarding the huge range of electrode configurations known for use in electroporation systems, including monopolar and bipolar configurations, see paragraph [0042] of US 2016/0296269 to Rubinsky.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL WAYNE FOWLER whose telephone number is (571)270-3201. The examiner can normally be reached Monday-Friday (9-5).
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/DANIEL W FOWLER/Primary Examiner, Art Unit 3794
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