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
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 11, 2026. Claims 1, 13-15, and 103-105 have been amended. Claims 4-6, 8-9, 16, and 21-101 have been canceled. Claim 106 is newly added.
Therefore, claims 1-3, 7, 10-15, 17-20, and 102-106 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.
Withdrawn- Specification Objection
In view of the concurrent submission of a substitute specification, removing all references to color drawings, the objections to the specification have been withdrawn.
Withdrawn- Drawings
In view of the concurrent submission of a substitute specification, the objections to the drawings have been withdrawn.
Withdrawn Claim Rejections - 35 USC § 112(a) – new matter
In view of Applicants' amendment to the instant application's claim set, removing recitation of “a negative charge” the rejections 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or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement has been withdrawn.
New Claim Rejections - 35 USC § 112(a) – new matter
Claims 1, and claims 2-3, 7, 10-20, and 102-106 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 claims 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 11, 2026.
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 “wherein said cells are stem cells and/or pre-osteoblast cells.” The amendment to claim 1 constitutes new matter. This is seen in part to the specification having no support for the species of pre-osteoblast cells. The specification provides express support for stem cells. For example, the specification identifies stem cells, satellite cells, myoblasts, osteoblasts, chondrocytes, fibroblasts, tenocytes, precursor cells, embryological cells, progenitor cells, mesenchymal stem cells, neural stem cells, glial progenitor cells, angioblast hematopoietic stem cells, induced pluripotent stem cells, allograft stem cells, and xenograft stem cells. The specification also separately identifies osteoblasts and “precursor cells” ([0004-0009]; [0016]; [0053]; [0104]).
However, the specification does not identify “pre-osteoblast cells” as a disclosed cell type. The disclosure does not identify osteoblastic precursor cells, pre-osteoblasts, or a population characterized as being at a pre-osteoblast stage, nor does the disclosure provide a description that would direct the ordinary artisan to select that particular species from the broader category of precursor cells. A pre-osteoblast is an immature, osteoblast-lineage precursor cell that has committed toward differentiation into a mature, bone-forming osteoblast. The specification identifies stem cells, osteoblasts, precursor cells, and progenitor cells, but does not identify “pre-osteoblast cells.” Although pre-osteoblast may fall biologically within the broader category of precursor or progenitor cells, generally, disclosure of these broader geniuses does not necessarily demonstrate possession of the specifically claimed pre-osteoblast species.
Applicant indicates generally “support for the amendments and newly added claim can be found throughout the application as originally filed, including the claims. No new matter is added.” 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, 10-15, 17-20, and 102-105 remain rejected, and claim 106 is newly 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, including adding new claim 106, in the response filed on June 11, 2026.
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 and differentiation, matrix formation or mineralization for in vitro or in vivo applications (Abstract). Kronberg additionally teaches the stimulation of stem cells (pg. 16, para. 2). 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).
Regarding the limitation “wherein said cells are stem cells and/or pre-osteoblasts cells,” Kronberg specifically teaches the application of these bioelectric devices where,
“wave patterns may be advantageously applied at both a macroscopic level (i.e. common bone fractures) as well as at microscopic levels (i.e. osteoblast development).” and,
“specific PEMF waveforms and frequencies that optimize osteoblast development. As described in greater detail in the Examples (see Example 1) the inventors demonstrate that PEMF signals enhance osteoblast mineralization and matrix production, and that the signal confers structural features as well.” (pg. 4-5, bridging para.)
Furthermore, Kronberg expressly teaches that “inactive pre-osteoblasts are present in resorption depressions” during the reversal stage of bone remodeling and that bone remodeling is influenced by electrical current and electromagnetic fields (pg. 9, para. 2). Kronberg further teaches electrical signals and waveforms for modulating biological tissues, including promoting proliferation and differentiation of bone cells (Abstract; pg. 7, para. 1-4; pg. 10, para. 1-3). Hence, the ordinary artisan would have been motivated to apply Kronberg’s electrical stimulation to pre-osteoblasts because pre-osteoblasts are expressly identified as cells participating in the electrically responsive bone-remodeling process, and stimulation of these cells would have predictably modulated their proliferation or progression toward active osteoblasts during bone formation.
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 the teachings 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 affect 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 teaches sinusoidal waves of 20-200Hz are typically employed to induce 1-l00 mV/cm electric fields in the repair site (pg. 2, last para.), operation in pulse-burst mode with burst repeated at 0.1-10 Hz (pg. 11, para. 4) or 5-100 Hz, 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.
Regarding claims 11 and 12, the teachings of Kronberg and Hargrave render claim 1 obvious. Kronberg additionally 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 further teaches analogous methods for delivering an agent into a cell through the application of nanosecond pulse electric fields ("nsPEFs") which 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, as well as other cell proliferative factors like erythropoietin pr insulin (column 3, lines 47-50; 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 13-15, 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.
Regarding claims 17-18, the teachings of Kronberg and Hargrave render claim 1 obvious. Beebe additionally teaches the method of electrical stimulation where 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, the teachings of Kronberg and Hargrave render claim 1 obvious. Kronberg explicitly teaches combining electrical stimulation methods with administration of additional biochemical agents, such as nitric oxide donors (pg. 31, last para.). Beebe further 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). In view of 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, the teachings of Kronberg and Hargrave render claim 1 obvious. 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 in a population of cells 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.
Regarding claim 106, the teachings of Kronberg and Hargrave render claim 1 obvious. Additionally, Kronberg teaches that the individual nearly square wave signal is asynchronous with a long positive segment and a short negative segment or vice versa (pg. 13, para. 5). Additionally, the ordinary artisan would have been motivated to employ a square wave pulse because the waveform provides a substantially constant electric field during the pulse duration with rapid rise and fall times, thereby implementing the predictable application of the desired nanosecond electric-field intensity, further in view of the teachings of Beebe. Bebbe teaches where the pulse is square wave (column 20, para. 2).
Response to Applicants’ Arguments as they apply to the rejections of claims 1-3, 7, 10-15, 17-20, and 102-105 under 35 USC§ 103
Applicant’s arguments filed June 11, 2026, have been fully considered but they are
not persuasive.
At pages 7-14 of the remarks filed on June 11, 2026, Applicants essentially argue the following:
Applicant argues that Kronberg uses exponentially decaying pulses whereas the present invention uses square wave pulses.
This argument is not persuasive with respect to claim 1 because claim 1 does not require a square-wave pulse. Regarding claim 106, Kronberg teaches that the individual nearly square wave signal is asynchronous with a long positive segment and a short negative segment or vice versa (pg. 13, para. 5). Additionally, the ordinary artisan would have been motivated to employ a square wave pulse because the waveform provides a substantially constant electric field during the pulse duration with rapid rise and fall times, thereby implementing the predictable application of the desired nanosecond electric-field intensity, further in view of the teachings of Beebe. Bebbe teaches where the pulse is square wave (column 20, para. 2). Bebbe additionally teaches almost-rectangular nanosecond pulses having rapid rise and fall times and nearly constant electric-field level during the pulse (column 7, para. 2). Thus, Beebe’s waveform teaching renders the square-wave limitation obvious with applied to the combined method.
Applicant argues that Hargrave concerns platelet activation and therefore would not have been consulted for stimulation of proliferating cells.
This argument is not persuasive because Hargrave is relied upon for its teaching of nanosecond pulsed electric field parameters and the relationship between those parameters and biological cellular responses. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Hargrave taches the dependence of nsPEF effects on cell type, pulse duration, rise time, electric field intensity, and other variables and discusses cellular signaling responses including calcium mobilization and growth related signaling. Kronberg explicitly teaches stimulating proliferation of osteoblasts, stem cells, progenitor cells, and related connective-tissue cell population.
Applicant argues that Hargrave and Beebe teach treatments resulting in cell death and therefore teach away from their use in a method intended to stimulate proliferation.
This argument is not persuasive because the cited references demonstrate that the biological effects of pulsed electric fields depend on the selected treatment parameters and cell type. In particular, the record identifies teachings of pulse duration, rise time, electric-field intensity, cell type, and pulse number as variables affecting the resulting cellular response. The fact that a particular nsPEF condition may cause apoptosis or other destructive effects does not establish that the reference discourages the use of nsPEF parameters generally for nonlethal cellular stimulation.
In response, the Examiner respectfully submits that patents are relevant as prior art for all they contain. "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). With that, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, even nonpreferred embodiments. See MPEP § 2123: Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989); Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005). In the instant case, the prior art recognizes that different parameter selections produce different biological effects, ranging from cell death to cell proliferation.
The prior art’s recognition that the response varies with the pulse parameters provides further motivation to optimize the application of one or more pulses of electricity to cells for the method of stimulating cell proliferation. This further demonstrates that the ordinary artisan would have found it obvious to apply known nanosecond pulse technology and known pulse parameters to Kronberg’s known proliferation method while selecting values appropriate to the desired proliferative response, as opposed to applying electrical stimulation inducing cell death or apoptosis.
Applicant further argues that combining Hargrave or Bebbe with Kronberg would result in massive cell death and render Kronberg inoperable for its intended purpose.
This argument is not persuasive because it again assumes that the ordinary artisan would be required to use conditions known and taught to cause destructive cellular effects. Kronberg teaches the intended proliferative cellular response, while Hargrave and Beebe teach known nanosecond pulse parameters and optimization of pulse duration, intensity, rise/fall time, and pulse number. The ordinary artisan would not have selected parameters known to destroy cells for a method of stimulating cell proliferation. Instead, the ordinary artisan would have selected the parameters taught in view of the desired biological response, not indiscriminately applied conditions taught for a clearly different purpose. The proposed combination does not require destruction of the treated cell population and does not render Kronberg’s method inoperable for its intended purpose.
Kronberg clearly states at the outset of the disclosure that:
“Compositions and methods are provided for modulating the growth, development and repair of bone, cartilage or other connective tissue. Devices and 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.”
Applicant’s argument that the ordinary artisan would have selected parameters to destroy cells is not persuasive.
Conclusion
Claims 1-3, 7, 10-15, 17-20, and 102-106 are rejected. No claims are allowed.
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 JOEL D LEVIN whose telephone number is (571)270-0616. The examiner be reached 8:00 am to 5:00 pm, Monday through Friday.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.D.L./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
Prosecution Insights