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 claims filed on May 19, 2026, have been acknowledged. Claims 1-32 and 34 were cancelled. Claims 33 and 38 were amended. Claims 33 and 35-38 are pending and examined on the merits.
Rejections and/or objections not reiterated from the previous office action mailed March 13, 2026, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from JP2020-001657 filed on January 8, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received July 1, 2022. While a certified copy of the foreign patent application JP2020-001657 is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 37 is 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 37 recites the limitation "the bone marrow mononuclear cells" in line 3. There is insufficient antecedent basis for this limitation in the claim. Claim 33, from which claim 37 depends, does not recite a bone marrow mononuclear cell. Instead, claim 37 is drawn to peripheral blood CD34+ cells. Claim 37 is interpreted to mean that peripheral blood CD34+ cells are administered, as recited in claim 33, and not bone marrow mononuclear cells.
Claim Rejections - 35 USC § 103
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 33, 35, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Cell Transplantation 23: 1599–1612. 2014), Seo et al. (Cell Transplantation 22: 1553–1568. 2013), Takeuchi et al. (Front. Hum. Neurosci. 9: 1-15. 2015), Kawase et al (J. Neural Eng. 14: 1-12. 2017), and Chen et al. (International Journal of Cardiology 201: 668–683. 2015). This is a new rejection made in response to Applicant’s amendments to claim 33. Applicant’s traversal has been considered but is moot in response to the new rejection of record.
Chen 2014 teaches that they treated fifteen patients with middle cerebral artery infarction 6 months to 5 years after a stroke by performing intracerebral administration of 3–8 × 106 human CD34+ immunosorted peripheral blood stem cells (PBSCs). Improvements in stroke scales (NIHSS, ESS, and EMS) and functional outcomes (mRS) from baseline to the end of the 12-month follow-up period were significantly greater in the PBSC than the control group. The fiber numbers asymmetry (FNA) scores based on diffusion tensor image (DTI) tractography were reduced in every PBSC-treated subject, but not in the control group. Reduction in the FNA scores correlated well with the improvement in NIHSS. Furthermore, this study also provided important evidence on the efficacy of PBSC implantation in improving stroke related motor deficits as a positive motor-evoked potential (MEP) response by transcranial magnetic stimulation (TMS) appeared in 9 of the 15 subjects in the PBSC group. This phase II study demonstrated that implantation of autologous CD34+ PBSC was safe, feasible, and effective in improving functional outcome (whole document).
Applicant’s specification discloses that “In the case of cerebral infarction, it is considered that the symptoms of cerebral infarction become stationary after, for example, 6 months from the onset, and a nervous function disorder remaining after, for example, 6 months have passed since the onset is defined as a sequela of cerebral infarction. Meanwhile, it is considered that, for example, 4 weeks after production of a cerebral infarction model of a mouse is equivalent to 6 months after the onset of cerebral infarction of a human.” (page 9 of specification). Figure 2 of Chen 2014 shows that all 15 of their patients exhibit hemiparesis (muscle weakness that affects one side of the body) at least 6 months after their stroke (Figure 2). Therefore, as each patient exhibits long term nervous function disorders at least 6 months after the stroke, each patient is considered to have a sequela of cerebral infarction.
Although Chen 2014 identifies that at least some of their patients underwent rehabilitation (page 1600, column 2, paragraph 4), Chen 2014 is silent regarding whether the rehabilitation included physical exercise using an assistive movement as part of their treatment regimen.
However, Seo teaches that they treated chronic hypoxic-ischemic brain injury in mice by administering adipose stem cells while also providing environmental enrichment (EE). The fate of transplanted cells and the levels of endogenous neurogenesis, astrocyte activation, and paracrine factors were also measured. As a result, EE and ASC transplantation synergistically improved rotarod latency, forelimb-use asymmetry, and grip strength compared to those of the other groups. The number of engrafted ASCs and bIII-tubulin+ neurons derived from the transplanted ASCs was significantly higher in mice in EE than those in SC. EE and ASC transplantation also synergistically increased BrdU+βIII-tubulin+ neurons, GFAP+ astrocytic density, and fibroblast growth factor 2 (FGF2) level. Hypoxic Ischemia brain damage was induced in 7-day-old mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min). Treatment began at 6 weeks of age (whole document). Based on Applicant’s specification, this timeframe would also equate to a sequela of cerebral infarction and would be equivalent to greater than 6 months after the infarction in humans (it is considered that, for example, 4 weeks after production of a cerebral infarction model of a mouse is equivalent to 6 months after the onset of cerebral infarction of a human.” (page 9 of specification)).
Seo teaches that EE mice were housed in a huge cage (86 × 76 × 31 cm) containing novel objects such as tunnels, shelters, and toys, and running wheels for voluntary exercise, allowing for social interaction (12–15 mice/cage) for up to 2 months (page 1555, column 2, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of administering CD34+ peripheral blood stem cells to patients suffering from hemiparesis at least 6 months after a stroke with an exercise routine as part of their rehabilitation regimen to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because both Chen 2014 and Seo teach treating a sequela of cerebral infarction using stem cells to improve stroke-related motor deficits. Furthermore, Seo teaches that EE and ASC transplantation synergistically improved neurobehavioral functions. The underlying mechanisms of this synergism included enhanced repair processes such as higher engraftment of the transplanted ASCs, increased endogenous neurogenesis and astrocytic activation coupled with upregulation of FGF2. Furthermore, Chen 2014 already identifies that that at least some of their patients underwent rehabilitation and that these could be maintained as part of the treatment method. Therefore, combining the method of administering stem cells to stroke patients of Chen 2014 with physical exercise, as identified by Seo, would have been obvious as this leads to a synergistic effect that improves treatment efficacy. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Chen 2014 and Seo do not teach wherein exercise is performed using an assistive movement device.
However, Takeuchi teaches that muscle activity-dependent stimulation is not applicable for the stroke patients with severe hemiparesis who have no voluntary muscle activation. Therefore, these patients require activity-dependent stimulation paradigms based on brain activity. It is postulated that the re-establishment of the disrupted sensorimotor loop by integrating movement intention and passive limb movement, assisted by a robot, will strengthen the associative connection (page 7, paragraph 2).
Kawase teaches a hybrid brain-machine interface exoskeleton for use in patients with paresis by combining EMG and EEG signals to control arm and hand movements, respectively
The hybrid BMI-based exoskeleton (BOTAS, as seen in figure 1; an assistive movement device) for paresis consists of an EEG-based controller (a voluntary control unit for neurotransmissions) for joints with no or little residual muscle activity, and an EMG-based controller (a voluntary control unit for muscle potential) for other joints with residual muscle activity. We used the BOTAS, which is an exoskeleton with six degrees of freedom to assist the whole arm and fingers (figure 1(a), bottom). In our previous study, sensorimotor rhythm, P300, and SSVEP (biological signals) were used to drive the exoskeleton for reaching and grasping movements (figure 1(a), left). The system allows users to trigger a registered motion of joints with no or little residual muscle activity by measuring EEG signals (uses sensors to measure EEG signal as seen in Figure 1a), processing them to identify the motion that will be performed (a processing unit), and using the EEG-based controller. They also implemented a new real-time control system based on estimation of joint angles using EMG signals measured by electrodes (a sensor) (figure 1(a), right). The new system enables users to control joints that utilize residual muscle activity. The EMG signal were processed (a processing unit) and used to estimate the flexion/extension angles of the elbow, wrist, and MP joint of the index finger (page 2, column 2, paragraph 3-page 6, column 1, paragraph 2 and Figure 1). Although Kawase does not specifically identify that their device comprises an actuator and a drive current generation unit, it is well understood that the device would include these components as Kawase does teach that the BOTAS device controls the forearm position by moving it towards the position of the estimated elbow angle at a constant velocity and controlled hand opening (page 5, column 1, paragraph 3-column 2, paragraph 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of administering CD34+ peripheral blood stem cells to patients at least 6 months after a stroke and having them perform physical exercise of the combined teachings of Chen 2014 and Seo with the BOTAS assistive movement device of Kawase to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Chen 2014 teaches that all fifteen of their patients have hemiparesis and Takeuchi teaches that muscle activity-dependent stimulation is not applicable for the stroke patients with severe hemiparesis who have no voluntary muscle activation. Therefore, these patients require activity-dependent stimulation paradigms based on brain activity. It is postulated that the re-establishment of the disrupted sensorimotor loop by integrating movement intention and passive limb movement, assisted by a robot, will strengthen the associative connection. As such, although Chen 2014 is silent regarding the severity of hemiparesis in their patients, it would have been obvious that the combined method of Chen 2014 and Seo could be used with patients with severe hemiparesis and that these pateints could use the BOTAS device of Kawase to promote the synergistic effects seen by Seo of combining stem cell administration and exercise in the weakened muscles. Furthermore, as stated by Takeuchi, this activity-dependent stimulation may help with the re-establishment of the disrupted sensorimotor loop by integrating movement intention and passive limb movement. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the limitation, “wherein the physical exercise promotes bidirectional feedback between central and peripheral nerves”, it is recognized the exercises using the BOTAS device would involve communication between central and peripheral nerves, promoting communication between the two.
The combined teachings of Chen 2014, Seo, Takeuchi, and Kawase do not teach wherein the CD34+ peripheral blood stem cells are administered intra-arterially.
However, Chen 2015 teaches that they transfused autologous peripheral blood-derived endothelial progenitor cells (PBDEPC) comprising cells that express CD34 (Figure 3) via the internal carotid artery and found that this treatment reduced brain-infarct zone (BIZ) and neurological deficit following ischemic stroke (IS) and that higher doses improved the sensorimotor functional results (whole document).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the intracerebral method of administering the CD34+ cells of Chen 2014 with the intra-arterial administration of Chen 2015 to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Chen 2015 teaches that intra-arterial administration of CD34+ peripheral blood progenitor cells was effective at treating cerebral ischemic infarction. Furthermore, intracerebral administration requires a complex system using a stereotaxic frame and a burr hole to administer the cells to a specific region of the brain whereas intra-arterial administration represents a much simpler method without the need for drilling a hole in the skull. Therefore, as Chen 2015 teaches that intra-arterial administration is effective, it would have been obvious to use intra-arterial administration as it is a much simpler procedure compared to intracerebral administration and it allows for repeat administrations over the course of treatment that may not be as accessible for intracerebral administration. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 37, Chen 2014 teaches that patients that received the CD34+ peripheral blood stem cells continued their rehabilitation program after the surgery which encompassed ~10 hours per week of rehabilitation and that the patients were kept for one day post-surgery before discharge (page 1600, column 2, paragraph 4-page 1602, column 1, paragraph 1). Furthermore, Seo teaches that their mice were transferred to the environmental enrichment cages post-surgery (page 1555, column 2, paragraph 1).
Therefore, it would have been well understood that the exercise could have been started within days after the transplantation was complete, well within the four weeks identified in claim 37.
Claims 33 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Cell Transplantation 23: 1599–1612. 2014), Seo et al. (Cell Transplantation 22: 1553–1568. 2013), Takeuchi et al. (Front. Hum. Neurosci. 9: 1-15. 2015), Kawase et al (J. Neural Eng. 14: 1-12. 2017), and Chen et al. (International Journal of Cardiology 201: 668–683. 2015) as applied to claim 33 above, and further in view of Perez-Rodriguez et al. (Expert Systems with Applications 41: 3922–3934. 2014). This is a new rejection made in response to Applicant’s amendments to claim 33. Applicant’s traversal has been considered but is moot in response to the new rejection of record.
The teachings of Chen 2014, Seo, Takeuchi, Kawase, and Chen 2015 are as discussed above.
The combined teachings of Chen 2014, Seo, Takeuchi, Kawase, and Chen 2015 do not teach wherein the assistive movement device performs feedback adjustment.
Perez-Rodriguez teaches that robotic devices are becoming a popular alternative to the traditional physical therapy as a mean to enhance functional recovery after stroke; they offer more intensive practice opportunities without increasing time spent on supervision by the treating therapist. An ideal behavior for these systems would consist in emulating real therapists by providing anticipated force feedback to the patients in order to encourage and modulate neural plasticity. Perez-Rodriguez developed an anticipatory assistance-as-needed control algorithm for a multijoint robotic orthosis to be used in physical acquired brain injury neurorehabilitation. This control algorithm, based on a dysfunctional-adapted biomechanical prediction subsystem, is able to avoid patient trajectory deviations by providing them with anticipatory force-feedback. The system has been validated by means of a robotic simulator. Obtained results demonstrate through simulations that the proposed assistance-as-needed control algorithm is able to provide anticipatory actuation to the patients, avoiding trajectory deviations and tending to minimize the degree of actuation. This new actuation paradigm avoids patient slacking and increases both participation and muscle activity in such a way that neural plasticity is encouraged and modulated to reinforce motor recovery (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the BOTAS device of the combined teachings of Chen 2014, Seo, Takeuchi, Kawase, and Chen 2015 with the assistance-as-needed control algorithm of Perez-Rodriguez to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Perez-Rodriguez teaches that robotic devices are used to enhance functional recovery after stroke as they offer more intensive practice opportunities without increasing time spent on supervision by the treating therapist. Perez-Rodriguez developed an anticipatory assistance-as-needed control algorithm for a multijoint (such as the BOTAS device) robotic orthosis to be used in physical acquired brain injury neurorehabilitation. This control algorithm, based on a dysfunctional-adapted biomechanical prediction subsystem, is able to avoid patient trajectory deviations by providing them with anticipatory force-feedback. This new actuation paradigm avoids patient slacking and increases both participation and muscle activity in such a way that neural plasticity is encouraged and modulated to reinforce motor recovery. As such, it would have been obvious to combine the BOTAS device with the algorithm of Perez-Rodriguez to enhance functional recovery after stroke by offering more intensive practice opportunities without increasing time spent on supervision by the treating therapist. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 33 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Cell Transplantation 23: 1599–1612. 2014), Seo et al. (Cell Transplantation 22: 1553–1568. 2013), Takeuchi et al. (Front. Hum. Neurosci. 9: 1-15. 2015), Kawase et al (J. Neural Eng. 14: 1-12. 2017), and Chen et al. (International Journal of Cardiology 201: 668–683. 2015) as applied to claim 33 above, and further in view of Arboix et al. (Expert Rev Neurother 9: 179-196. 2009). This is a new rejection made in response to Applicant’s amendments to claim 33. Applicant’s traversal has been considered but is moot in response to the new rejection of record.
The teachings of Chen 2014, Seo, Takeuchi, Kawase, and Chen 2015 are as discussed above.
The combined teachings of Chen 2014, Seo, Takeuchi, Kawase, and Chen 2015 do not teach wherein cerebral infarction is from a lacunar infarction.
However, Arboix teaches that lacunar infarcts or small subcortical infarcts result from occlusion of a single penetrating artery and account for one quarter of cerebral infarctions. Patients with a lacunar infarct usually present with a classical lacunar syndrome (pure motor hemiparesis, pure sensory syndrome, sensorimotor stroke, ataxic hemiparesis or dysarthria–clumsy hand) and, less frequently, an atypical lacunar syndrome.
As Lacunar infarcts are associated with a quarter of cerebral infarcts and can lead to hemiparesis, it would have been well understood by one of ordinary skill in the art that the combined method of Chen 2014, Seo, Takeuchi, Kawase, and Chen 2015 could be used to treat patients that experience lacunar infarction with hemiparesis. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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.
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/KEENAN A BATES/Examiner, Art Unit 1631
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