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
Status of Claims
Claims 1-19 are pending and under examination in the instant office action.
Claim Objections
Claim 7 is objected to because of the following informalities: typographical errors. The recitation “the muscle wasting is damage due to artificial ventilation from ventilator-induced diaphragm dysfunction (VIDD) or ventilator-induced lung injury (VILI)” should be corrected to -- the muscle wasting is induced by damage due to artificial ventilation wherein the damage due to artificial ventilation is ventilator-induced diaphragm dysfunction (VIDD) or ventilator-induced lung injury (VILI)-- in light of specification (see [0011]).
Claim Rejections - 35 USC § 112 (b)
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 16 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 pre-AIA the applicant regards as the invention.
Claim 16 recites the limitation "the multiple dose" in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 9 from which it depends does not recite “multiple dose”. If it is amended to be dependent from claim 14, the rejection will be overcome.
For the examination purpose, it is treated as if it is dependent from claim 14.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 10, and 18-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2019/0125803 (hereafter, BRODIE).
BRODIE teaches a method of treating, preventing or ameliorating a muscle-associated disease or damage in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising isolated extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) wherein said muscle-associated disease or damage is selected from the group consisting of: a motor neuron disease characterized by gradual muscle weakening and wasting, uncontrolled twitching and eventually loss of control of voluntary movement, a muscular dystrophy, spinal cord injury, muscle wasting, cardiac muscle injury, inflammatory myopathy, myasthenia gravis, sarcopenia, cachexia, fibrosis, smooth muscle injury, and skeletal muscle injury (abstract, [0007],[0031], [0033], [0047], and claims 37, 40 and 42). The term “extracellular vesicles” refers to all cell-derived vesicles secreted from MSCs including but not limited to exosomes and microvesicles ([0079]).
BRODIE specifically discloses the use of MSCs and their exosome to treat cachexia, which is weakness or wasting of the muscles of the body due to chronic illness or cancer, and coculture with UC- and CH-MSCs or their exosomes abrogated these cachexic effects, as decreased cell death, and increased differentiation and myosin heavy chain expression were observed (Example 9, [0221]-[0222]).
BRODIE further teaches that the EVs are vesicles obtained from mesenchymal stem cell (MSC) wherein the MSC refers to multipotent stromal stem cells and is derived from bone marrow, adipose tissue, amniotic placenta, chorionic placenta, or umbilical cord ([0003], [0049], [0077], and [0201]). In some embodiments, the cell is a human cell ([0050]).
BRODIE teaches that exosomes, extracellular vesicles, or microvesicles can be obtained by growing MSCs in culture medium with serum depleted from exosomes or in serum-free media such as OptiMeM and subsequently isolating the exosomes by ultracentrifugation ([0081] and [0179]).
BRODIE discloses intramuscular injection of 5×105 MSCs or their exosomes ([0038], Example 1, [0186]).
BRODIE discloses a pharmaceutical composition comprising an isolated extracellular vesicle and a pharmaceutically acceptable carrier or adjuvant ([0028]-[0030] and claims 38-39).
As such, the instant claims are anticipated by BRODIE.
Claims 1, 10, 12-17, and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018195210 A1 (hereafter, MARBÁN).
MARBÁN teaches a method for treating Duchenne muscular dystrophy (muscle wasting disease) and Becker muscular dystrophy, and symptoms or disease states associated therewith (including skeletal muscle myopathy associated with Duchenne muscular dystrophy) in a patient in need thereof, the method comprising administering cardiosphere-derived cells (CDC), extracellular vesicles derived therefrom (e.g., exosomes, etc.), and/or combinations thereof to the patient (abstract, [0003], [0004], [0006], [0007] and claims 35 and 37). MARBÁN further teaches that administration of CDCs and/or CDC-exosomes (XOs) delays the onset of muscular dysfunction (including in skeletal muscle dysfunction) and/or maintains, improves, and/or restores muscular function and integrity (including in skeletal muscles) in the subject having a dystrophinopathy and dystrophic skeletal muscles of the patient that are treated include one or more of the diaphragm, the limb muscles (e.g., in the arms and/or legs), and/or torso muscles ([0006] and [0023]). MARBÁN further teaches that CDC mediates their therapeutic effects via secreted vesicle exosomes in retarding or reversing Duchenne muscular dystrophy ([0227] and Fig. 9A).
MARBÁN teaches that the CDCs, CDC-XOs, and/or CDC-EVs are autologous or allogeneic to the subject (e.g., derived from their own tissue, from another subject's tissue, and/or from the tissue of another animal species) ([0008]).
MARBÁN discloses that the CDCs, CDC-EVs, and/or CDC-XOs are delivered to the subject systemically and locally and in some embodiments, they are injected or infused intravenously ([0009] and claim 44).
MARBÁN teaches that the administration of CDCs, CDC-EVs, and/or CDC- XOs to a subject in need thereof includes a single dose and/or multiple doses (e.g., 2, 4, 6, 8, 10, or more doses) ([0010] and claims 39-40). MARBÁN discloses that the administration of the multiple doses starts with a first dose and continues with a second dose, wherein the administration (one or more times) alters expression of one or more markers of T cell activation or proliferation, the markers comprising CD69 and/or HLA-DR ([0022], [0351], and claim 112).
MARBÁN discloses that the number of CDC-EVs or CDC-XOs administered in each dose (where a single or multiple doses are used) and/or over the course of a treatment regimen is equal to or at least about: 1 x 106, 1 x 107, 1 x 108, 1 x 109, 1 x 1010, 1 x 1011, 1 x 1012, or ranges including and/or spanning the aforementioned values ([0012] and [0014]). MARBÁN further discloses that "a therapeutically effective amount of CDCs" is a sufficient amount of CDCs administered to a subject to result in delivery of a sufficient amount of EVs to a targeted dystrophic skeletal muscle in a subject to increase and/or restore skeletal muscle function in the subject and to immune-modulate chronic inflammatory immune response ([0266]).
MARBÁN discloses that to generate exosomes, human CDCs were cultured until confluency at passage 5; the cells were washed with DPBS, and the media was supplanted to serum-free media; CDCs were then cultured in physiologically low oxygen (2% O2) for 24 hours; the conditioned media was then collected, sterile filtered using a 0.45 μm filter, and frozen for later use; later, the conditioned media was thawed and the exosomes were purified and concentrated by ultrafiltration via centrifugation using 3 kDa centrifugal filters (EMD Millipore) ([0257] and [0279]).
MARBÁN discloses a pharmaceutical composition comprising a CDC-XO or a CDC- derived extracellular vesicle (CDC-EV) and a pharmaceutically acceptable carrier ([0034] and claims 85 and 94).
As such, the instant claims are anticipated by MARBÁN.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
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 of this title, 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 4, 11, and 18 are rejected under 35 U.S.C. 102 (a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103(a) as obvious over US 2019/0125803 (hereafter, BRODIE).
BRODIE as applied supra is herein applied for the same teachings in their entirety.
As to claim 4, the claim further recites the EVs are obtained from bone marrow-derived mesenchymal stromal cells of the subject experiencing muscle wasting. However, it appears that the EV of the prior art is the same as claimed regardless of the source of bone marrow-derived mesenchymal stromal cells. There is no indication of any structural difference resulted from such source. When the reference teaches a product that appears to be the same as, or an obvious variant of, the product set forth in a product-by-process claim although produced by a different process, either 102 or 103 rejection can be properly made. See In re Marosi, 710 F.2d 799, 218 USPQ 289 (Fed. Cir. 1983) and In re Thorpe, 777 F.2d 695, 227 USPQ 964 (Fed. Cir. 1985). See also MPEP §2113. In the alternative, it would have been obvious to use bone marrow-derived mesenchymal stromal cells of the subject experiencing muscle wasting or other subjects for obtaining EVs on the reasonable expectation that similar EVs would be obtained from the same type of cells.
As to claims 11 and 18, the claim further recites how the EV is obtained. As stated in the above 102 rejection, BRODIE teaches that exosomes, extracellular vesicles, or microvesicles can be obtained by growing MSCs in culture medium with serum depleted from exosomes or in serum-free media such as OptiMeM and subsequently isolating the exosomes by ultracentrifugation ([0081] and [0179]). Thus, BRODIE teaches the same EVs derived from bone-marrow-derived mesenchymal stromal cells, obtained by almost identical process using the same cells and same medium as claimed although the reference is silent about detailed steps about filtering, freezing and thawing as recited in the instant claim 11. Also, it does not appear that there is any difference in EVs resulting from the claimed process from those of the prior art. When the reference teaches a product that appears to be the same as, or an obvious variant of, the product set forth in a product-by-process claim although produced by a different process, either 102 or 103 rejection can be properly made. See In re Marosi, 710 F.2d 799, 218 USPQ 289 (Fed. Cir. 1983) and In re Thorpe, 777 F.2d 695, 227 USPQ 964 (Fed. Cir. 1985). See also MPEP §2113.
As such, claims 4, 11 and 18 are anticipated by or, in the alternative, obvious over BRODIE.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0125803 (hereafter, BRODIE) in view of WO 2018195210 A1 (hereafter, MARBÁN) as evidenced by Power et al. (Am J Physiol Regul Integr Comp Physiol 305: R464–R477, 2013).
BRODIE as applied supra is herein applied for the same teachings in their entirety.
As to claim 4, BRODIE does not specifically teach that the EVs are obtained from bone marrow-derived mesenchymal stromal cells of the subject. However, it was known in the art that the exosomes and/or EVs can be derived from their own tissue, from another subject's tissue, and/or from the tissue of another animal species as evidenced by MARBÁN ([0008]). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to obtain EVs from the patient’s own bone marrow-derived mesenchymal stromal cells or those of another subject for treating the patient experiencing muscle wasting as taught by MARBÁN. The skilled artisan would have reasonably expected that similar EVs would be obtained from the same type of cells.
As to claim 5-7, BRODIE does not specifically disclose that the subject is exposed to a prolonged immobilization characterized by muscular atrophy or undergoing positive pressure mechanical ventilation, or the muscle wasting is induced by damage due to artificial ventilation such as ventilator-induced diaphragm dysfunction (VIDD) or ventilator-induced lung injury (VILI).
However, it was well known in the art that muscle wasting can be caused by a prolonged immobilization, positive pressure mechanical ventilation (MV) or ventilator-induced diaphragm dysfunction (VIDD) as evidenced by Power et al. (abstract). Power et al. teach that prolonged MV can promote diaphragmatic atrophy and contractile dysfunction, which is referred to as ventilator-induced diaphragm dysfunction (VIDD) and only 18–24 h of MV is sufficient to develop VIDD in both laboratory animals and humans (abstract). Power et al. further teach that prolonged MV results in rapid atrophy of diaphragm muscle fibers in humans (R466, col 2, para 1).
Also, MARBÁN teaches a method for treating Duchenne muscular dystrophy (muscle wasting disease) and Becker muscular dystrophy, and symptoms or disease states associated therewith (including skeletal muscle myopathy associated with Duchenne muscular dystrophy) in a patient in need thereof, the method comprising administering cardiosphere-derived cells (CDC), extracellular vesicles derived therefrom (e.g., exosomes, etc.), and/or combinations thereof to the patient (abstract, [0003], [0004], [0006], [0007] and claims 35 and 37). MARBÁN further teaches that administration of CDCs and/or CDC-exosomes (XOs) delays the onset of muscular dysfunction (including in skeletal muscle dysfunction) and/or maintains, improves, and/or restores muscular function and integrity (including in skeletal muscles) in the subject having a dystrophinopathy and in some embodiments, dystrophic skeletal muscles of the patient that are treated include one or more of the diaphragm, the limb muscles (e.g., in the arms and/or legs), and/or torso muscles ([0006] and [0023]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use EVs for a subject experiencing muscle wasting due to prolonged immobilization, undergoing positive pressure mechanical ventilation, or ventilator-induced diaphragm dysfunction (VIDD) because those are known to cause similar muscle wasting and EV was taught to be effective for maintaining, improving, and/or restoring muscular function and integrity in skeletal muscles including diaphragm as evidenced by BRODIE and MARBÁN. The skilled artisan would have reasonably expected that EVs would be similarly effective for treating muscle wasting in those subjects.
As to claims 8-9, BRODIE does not specifically teach the specific amount of EVs per kg of subject body mass. Also, BRODIE does not specifically teach administering EVs as a single or multiple doses recited in claims 10-15.
MARBÁN also discloses that the number of CDC-EVs or CDC-XOs administered in each dose (where a single or multiple doses are used) and/or over the course of a treatment regimen is equal to or at least about: 1 x 106, 1 x 107, 1 x 108, 1 x 109, 1 x 1010, 1 x 1011, 1 x 1012, or ranges including and/or spanning the aforementioned values ([0012] and [0014]). MARBÁN further discloses that "a therapeutically effective amount of CDCs" is a sufficient amount of CDCs administered to a subject to result in delivery of a sufficient amount of EVs to a targeted dystrophic skeletal muscle in a subject to increase and/or restore skeletal muscle function in the subject and to immune-modulate chronic inflammatory immune response ([0266]). MARBÁN teaches that the administration of CDCs, CDC-EVs, and/or CDC- XOs to a subject in need thereof includes a single dose and/or multiple doses (e.g., 2, 4, 6, 8, 10, or more doses) ([0010] and claims 39-40). MARBÁN discloses that the administration of the multiple doses starts with a first dose and continues with a second dose, wherein the administration (one or more times) alters expression of one or more markers of T cell activation or proliferation, the markers comprising CD69 and/or HLA-DR ([0022], [0351], and claim 112).
As to the amount of EVs, MARBÁN discloses the range overlapping those claimed (when the average adult weight is about 60 kg, the dose of 1 x 1012 /60 is converted to 1.67 x 1010 per kg of subject body mass, which falls within the claimed range). Based on the dosage taught by MARBÁN, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to find out the amount of EVs sufficient for maintaining, improving, and/or restoring muscular function depending on affected skeletal muscles including diaphragm and severity of the muscle damage. Also, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize initial dose and maintenance dose of EVs and to adjust dosing frequency based on the patient’s response such as differences in expression of biomarkers because MARBÁN already teaches that the EVs can be administered in a single dose or multiple doses and administration (one or more times) of EVs alters expression of one or more markers of T cell activation or proliferation (e.g., CD69 and/or HLA-DR).
In addition, it is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket, 33 USPQ 33; In re Russell, 169 USPQ 426. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
As to claim 12, BRODIE does not specifically teach administering the EV intravenously to the subject. However, MARBÁN discloses that EVs, and/or exomes can be administered via intravenous injection as well as intramuscular injection directly at a skeletal muscle for treating muscle wasting disease such as Duchenne muscular dystrophy (abstract, [0003], [0004], [0006], [0007], [0009] and claims 35, 37, and 44). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer EVs of BRODIE via intravenous injection for a subject experiencing muscle wasting because intravenous injection was known to be suitable for delivering EVs in the treatment of muscle wasting conditions as evidenced by MARBÁN.
Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-19 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-15 of copending application 19/222305.
Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims of ‘305 application are drawn to a method of administering bone marrow-derived mesenchymal stromal cell (BM-MSC) derived extracellular vesicles (EVs) to a subject experiencing at least one of ventilator induced diaphragm dysfunction, critical illness myopathy, sarcopenia, and cancer cachexia (muscle wasting conditions) and a composition comprising: bone marrow-derived mesenchymal stromal cell (BM-MSC) derived extracellular vesicles (EVs); and, at least one pharmaceutical excipient.
As to claims 11 and 18, the claim further recites how the EV is obtained. The claims of ‘305 application recite the same extracellular vesicles obtained from the same cells as the instant claims. Also, it does not appear that there is any difference in EVs resulting from the claimed process from those of ‘305 application. When the reference teaches a product that appears to be the same as, or an obvious variant of, the product set forth in a product-by-process claim although produced by a different process, either 102 or 103 rejection can be properly made. See In re Marosi, 710 F.2d 799, 218 USPQ 289 (Fed. Cir. 1983) and In re Thorpe, 777 F.2d 695, 227 USPQ 964 (Fed. Cir. 1985). See also MPEP §2113. Thus, the instant claims 11 and 18 read on the method and the composition recited in ‘305 application.
As such, the instant claims are anticipated by the claims of the co-pending application.
Conclusion
No claims are allowed.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611