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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 16, 2025 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on June 16, 2025. Claims 2-6, 8-9 and 21-101 have been canceled.
Therefore claims 1-3, 7, 10-20, and 102-105 are currently under examination.
Priority
The present application filed 07/07/2021 is a CON of PCT/US2020/013030, filed on 01/10/2020, which claims benefit to provisional application 62/790,865, filed on 01/10/2019.
Thus, the earliest possible priority for the instant applications is 01/10/2019.
New Specification Objection
The disclosure is objected to because of the following informalities: The specification
references color drawings, specifically referring to Fig. 3, See [0020] and [0099]. Necessary correction is required. Applicant may obviate the objection by filing the petition for color drawings.
Drawings Objection
Regarding to color drawings, the petition under 37 CFR 1.84(a)(2) and (b)(2) to “Accept
Color Photographs” does not appear to have been filed. The drawings are objected to under 37 CFR 1.83(a) because they fail to show color designated and as described in the specification, see Fig. 3. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings 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).
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 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: Additionally, any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing
sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid
abandonment of the application. Any amended replacement drawing sheet should include all of
the figures appearing on the immediate prior version of the sheet, even if only one figure is being
amended. The figure or figure number of an amended drawing should not be labeled as
“amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from
the replacement sheet, and where necessary, the remaining figures must be renumbered and
appropriate changes made to the brief description of the several views of the drawings for
consistency. Additional replacement sheets may be necessary to show the renumbering of the
remaining figures. Each drawing sheet submitted after the filing date of an application must be
labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR
1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and
informed of any required corrective action in the next Office action. The objection to th e
drawings will not be held in abeyance.
New Claim Rejections - 35 USC § 112(a) – new matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, and claims 2-3, 7, 10-20, and 102-105 by dependence, are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is new matter rejection necessitated by amendment filed June 16, 2025.
37 CFR 1.118 (a) states that "No amendment shall introduce new matter into the disclosure of an application after the filing date of the application".
Claim 1 is directed to a method requiring that each pulse of electricity has “a negative charge.” The amendment to claim 1 constitutes new matter. This is seen in part to the specification having no support for any pulse polarity, a negative-only pulse, or a pulse having “negative charge.” The specification describes pulse intensity ranges, including about 1.0 kV/cm to about 30.0 kV/cm, pulse durations between about 1 ns and about 1,000 ns, frequencies between about 0.01 Hz and about 1,000 Hz, pulse counts including up to 150 pulses and five or fewer pulses, and control of rise- and fall-times through pulse-shape design ([0038-0036]). Additionally, the working examples likewise describe five 300 ns pulse at specified field strengths, but do not describe a “negative charge” ([0051-0053]; [0089-0107]).
Applicant indicates support for the amendment can be found in claim 6 and Fig.1, but this is not the case. The entirety of the disclosure does not provide any support for this claim element and is thus considered new matter.
MPEP §2163.06 notes:
If new matter is added to the claims, the examiner should reject the claims under 35
U.SC. 112, first paragraph - written description requirement. In re Rasmussen, 650 F2d 1212, 211 USPQ 323 (CCPA 1981).
MPEP §2163.02 teaches that:
Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed. If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application.
MPEP §2163.06 further notes:
When an amendment is filed in reply to an objection or rejection based on 35 U.SC. 112, first paragraph, a study of the entire application is often necessary to determine whether or not ''new matter" is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure. (Emphasis added).
Modified and Maintained Claim Rejections - 35 USC§ 103
Claims 1-3, 7, 10-20, and 102-105 are rejected under 35 U.S.C. 103 as being unpatentable over Kronberg et al. (WO 2006/132855 A2), in view of Hargrave et al. (US 2011/0318319 A1), and Beebe et al. (US 8,822,222 B2). This is a modified rejection necessitated by Applicants’ amendments to the claims in the response filed on June 16, 2025.
Regarding claim 1-3, 7, 10 and 102-103, Kronberg teaches methods for modulating the growth and development of tissue using pulsed (electromagnetic) stimulation. In particular, Kronberg teaches methods for modulating osteochondral development using pulsed electromagnetic field therapy, for modulating the growth, development and repair of bone, cartilage or other connective tissue. Stimulus waveforms are provided to differentially modulate the behavior of osteoblasts, chondrocytes and other connective tissue cells to promote proliferation, differentiation. matrix formation or mineralization for in vitro or in vivo applications (abstract). Specifically, Kronberg teaches sinusoidal waves of 20-200Hz are typically employed to induce 1-100m V/cm electric fields (pg. 2, para. 5), and additional modes of operation in overlapping ranges (pg.11, para 3-5).
Moreover, the ordinary artisan would have recognized the utility nanosecond pulse parameters for stimulation of cellular proliferation were well known in the prior art, further in view of Hargrave.
Hargrave expressly teaches methods involving the use of nanosecond pulsed electric fields (nsPEFs) with pulse durations ranging from approximately 10 picoseconds to 10 microsecond (1,000 nanoseconds) and electric field intensities ranging from 10 kV/cm to 350 kV/cm to stimulate cellular responses, including growth factor signaling and enhanced cell proliferation for wound healing purposes ([0002]). These teachings fully encompass the claimed pulse durations (10 ns-1,000 ns) of claim 1 and the narrower sub-range (10 ns-300 ns) of claim 2. Hargraves additionally teaches the applicability of similar electrical stimulation for generalized cellular responses, such as to activate growth through innate cellular responses such as ‘Calcium mobilization’ ([0002]; [0031]).
Principally, Hargrave explicitly discloses,
“The effects of nsPEFs on cells differ depending on the cell type, pulse duration and risetime, electric field intensity, and/or other factors ([0033]).”
“The optimum pulse duration will vary depending on the cell type, tissue type, and desired treatment, among other factors ([0038]).”
Furthermore, the specific cellular responses taught to be induced by the methods of Hargrave, such as calcium mobilization, were well recognized in the field to be related to cellular proliferation ([0039]).
Where a variable is disclosed in a range in the prior art is taught, there exists a prima facie case of obviousness based on optimization where the variable was recognized in the prior art to be a result-effective variable. That is to say that the particular parameter was taught and known to affected the result. A person of ordinary skill in the art would have found it obvious to use the explicated teachings to have optimized for the parameters or result effective variables, as demonstrated above.
While Hargrave does not explicitly recite pulse frequencies, Kronberg’s teachings complement this by providing explicitly frequency ranges (0.01 Hz-1,000 Hz) as recited in claim 3, thereby making the selection of these specific parameters an obvious and predictable optimization. The combination of Kronberg and, Hargrave renders the claimed invention prima facie obvious. Prior to the effective filing date, it would have been prima facie obvious to the ordinary artisan to simply apply Kronberg’s teachings of methods for modulating tissue growth and development using pulsed electromagnetic stimulation, including the application of sinusoidal waveforms withing a broad frequency ranges with Hargrave’s teachings of the use of nanosecond pulsed electric fields (nsPEFs) with durations ranging from 10 ps to 10µs and electric field intensities between 10 kV/cm and 350 kV/cm to stimulate cellular responses, including enhanced proliferation.
Since Kronberg teaches that electrical stimulation promoted cell proliferation, an ordinary artisan would have recognized combining the frequency ranges taught by Kronberg with the nanosecond pulsed electric field parameters and technologies disclosed by Hargrave would predictably enhanced cellular stimulation. The optimization of pulse duration and intensity within the known nanosecond and microsecond ranges was a routine design choice, as these parameters were already recognized in the prior art as result-effective variables influencing cellular proliferation.
Furthermore, Hargrave explicitly teaches the application of nanosecond pulsed electric fields (nsPEFs) with intensity peaks ranging from 10 kV/cm to 350 kV/cm, which fully encompasses the claimed ranges of 1.0-30.0 kV/cm, 1.0-25.0 kV/cm, and 2.5-25.0 kV/cm (abstract; [0033]; [0037]). Hargrave explicitly teaches the electric pulses within the claimed field strength ranges effectively stimulate cellular responses, making it obvious for a person of ordinary sill in the art to apply such intensities in Kronberg’s cell proliferation method.
The instant claims are amended to recite that the pulses have a “negative charge.” According to the broadest reasonable interpretation, the ordinary artisan would understand the recitation of “negative charge” to broadly refer to features such as negative polarity, a net negative waveform, or a negative phase. Although Fig. 1 illustrates an example of an electric-field waveform, the claim language “negative charge” does not correspond to a clearly understood electrical parameter (instant specification [0091]). The figure appears to show a negative-polarity electric field pulse rather than a pulse having “negative charge.” However, to the extent this limitation is interpreted as requiring a pulse having a negative polarity or a negative electric-field component, the limitation does not distinguish the claimed invention from the teachings of Kronberg and Hargrave. Electrical pulses in the prior art, including those generated by nsPEF systems, implicitly include positive or negative polarity waveforms or waveform components depending in circuit configuration. Thus, a pulse having a negative electric-field component would have been an expected and routine waveform characteristic of pulsed electric field systems.
Regarding claims 11 and 12, the teachings of Kronberg and Hargrave render claim 1 obvious. Kronberg teaches the application of pulsed electric fields for stimulating cell proliferation and establishes motivation to optimize pulse characteristics for biological cellular effects. Hargrave explicitly discloses nanosecond pulsed electric fields with durations between 10 picoseconds and 1 microsecond, implicitly requiring fast rise and fall times to maintain short pulse durations.
Moreover, Beebe teaches analogous methods for delivering an agent into a cell through the application of nanosecond pulse electric fields ("nsPEFs"). The taught methods are directed to enhancing gene expression in a cell and a nucleic acid introduced into the cell may also modulate cell proliferation (abstract, column 3, line 45, and column 9, line 38). Furthermore, Beebe teaches the nsPEFs can range in time from 1 to 1000 nanoseconds, preferably 1 to 300 nanoseconds, and can also range in electric field intensity from 1 to 1000 kV/cm, preferably 10 to 350 kV/cm (column 4, lines 39-42). While the teachings of Beebe relate modulation as a targeting mechanism for hyperproliferating cells by the introduction of an agent to suppress the hyperproliferative disease, it is also taught that agents delivered in the form a polypeptide comprising a hormone, a cytokine, a lymphokine, a growth factor, or a combination thereof (column 3, lines 47-50), as well as other cell proliferative factors like erythropoietin pr insulin (column 9, lines 20-21).
Beebe precisely teaches the rise times of classical electroporation pulses are generally longer than the charging time of the cell membrane and, therefore, will not allow an electric field to reach into the cell. By contrast, nsPEF pulses are almost rectangular pulses in the nanosecond range, preferably 10 to 300 nanoseconds (ns), with rapid rise times, short compared to the charging time of the outer cell membrane and ranging from 1 to 30 nanoseconds (ns) and high electric fields ranging from about 1 to 1000 kV/cm, preferably about 10 to 350 kV/cm. Beebe explicitly teaches except for the fast rise and fall times of the pulses, the field strength during the pulse remains at a nearly constant level (column 7, lines 20-30). Beebe additionally teaches particular means and motivations for optimization, such as the effects of nsPEFs on cells differing depending on such factors as cell type, pulse duration and rise-time, electric field intensity, and the number of pulses (column 8, lines 42-44).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results. In this case, the methods of Kronberg, Hargrave, and Beebe all teach directly to the application of nanosecond ranged electric pulse application for cellular physiological modifications, including cellular proliferation.
Regarding claims 13-16, the teachings of Kronberg and Hargrave render claim 1 obvious.
Kronberg teaches that pulsed electric fields can be applied both in vivo and in vitro, as well as those electrically stimulated cells being transplanted into a subject for therapeutic purposes (pg. 6, lines 15-17; pg. 14-15, bridging paragraph; pg. 22, first para.), making the additional step of implanting treated cells an expected extension of known teachings. Additionally, Kronberg explicitly teaches the method where cells are osteoblast, chondrocytes (abstract), as well as other cell types such as precursor cells such as stem cells, uncommitted progenitors, committed progenitor cells, multipotent progenitors, pluripotent progenitors or cells at other stages of differentiation (pg. 16, lines 8-20). Again, it is prima facie obviousness exemplary rationale to combine prior art elements according to known methods to yield predictable results and apply a known technique to a known method in the same way.
Regarding claims 17-18, the teachings of Kronberg and Hargrave render claim 1 obvious. Further, the optimization of the range and number of pulses was well known, as expressed in evidentiary teachings. Beebe specifically teaches the method of claim 1 and identifies electric field pulses comprises 1 to 100 pulses (claims 17-18). Since both Kronberg and Beebe recognize that the number of applied pulses influences the biological outcome, it would have been obvious to one skilled in the art to select a specific number of pulses as a predictable optimization to achieve the desired cellular response.
Regarding claims 19-20, Kronberg explicitly teaches combining electrical stimulation methods with administration of additional biochemical agents, such as nitric oxide donors (pg. 31, last para.). More specifically, Beebe teaches the method for utility for introducing an agent into a cell (claim 1), where the agent is a macromolecular complex, nanocapsules, microcapsules, microspheres, beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, Liposomes (column 14, para. 3), viral particles (column 8, para. 3), and, more broadly the agent can be drugs (e.g., chemotherapeutic agents), nucleic acids (e.g., polynucleotides), and peptides and polypeptides (including antibodies) (column 9, para. 2).
Given these teachings, it would have been obvious for the skilled artisan to include additional agents, as claimed, in Kronberg’s electric pulse treatment, as the co-administration of such agents with electric stimulation was well-known and predictable to enhance or tailor the biological effects.
Regarding claims 104 and 105, Kronberg and Hargrave both teach that cellular responses, including proliferation, occur after electrical stimulation, suggesting observations periods within standard biological timeframes, such as 24-48 hours post-treatment. Given the predictable nature of cellular growth cycles and well-established practice in cell culture studies, observing proliferation at about 24 hours or 48 hours after stimulation is an obvious and routine measurement step, reflecting inherent biological timing rather than an inventive activity.
Response to Applicants’ Arguments as they apply to the rejections of claims 1-3, 7, 10-20, and 102-105 under 35 USC§ 103
Applicant's arguments filed June 16, 2025, have been fully considered but they are
not persuasive.
At pages 5-13 of the remarks filed on June 16, 2025, Applicants essentially argue the following:
Applicant argues that the applied references do not teach applying pulses to stimulate cell proliferation.
This argument is not persuasive because Kronberg explicitly teaches stimulation of cell growth, differentiation, and matrix formation in osteoblasts and other connective tissue cells using electrical stimulation. Hargrave further teaches nanosecond pulsed electric fields producing cellular responses including growth related signaling pathways. Furthermore, the cell proliferation increases claimed are broad and claimed with no reference against which the increase is measured. The applied references teach electrical stimulation producing proliferative cellular responses.
Applicant argues the references do not disclose the claimed pulse parameters.
This argument is not persuasive because Hargrave teaches nsPEF pulses with durations from 10 ps to 10 µs and field strengths 10-350 kV/cm, which encompass the claimed pulse ranges. It is not inventive to find optimal workable ranges by routine experimentation. See In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955). Where numerical ranges overlap or lie inside ranges disclosed by the prior art, a prima facie case of obviousness exists.
Applicant argues Hargrave relates only to platelet activation.
This argument is not persuasive because Hargrave teaches broader cellular responses including growth factor signaling and calcium mobilization, which the ordinary artisan would have recognized as signaling pathways associated with cellular proliferation. Hence, the reference is relevant to stimulation of cellular responses including proliferation.
Applicant agues the references do not teach the amended “negative charge” limitation.
This argument is not persuasive because the term “negative charge” is interpreted under the broadest reasonable interpretation, and to the extend the limitation is interpreted as a pulse having a negative polarity or negative electric field component, such waveform characteristics are inherent and routine in pulsed electric-fiend systems. This limitation does not distinguish the instant claims over the prior art.
Conclusion
Claims 1-3, 7, 10-20, and 102-105 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOEL D LEVIN whose telephone number is (571)270-0616. The examiner can normally be reached Fulltime Teleworker.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.D.L./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633