DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-16 are pending, all of which have been considered on the merits.
Priority
Acknowledgement is made of Applicants’ claim for benefit as a continuation under 35 USC 120 to prior-filed US Application No. 17/335477 (filed 6/1/2021, now abandoned).
Drawings
The replacement drawings submitted 7/15/2024 have been received and entered. The replacement drawings contain color images. The drawings are objected to for containing color images without a petition for acceptance of color drawings.
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 EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web, 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:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) 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).
Claim Interpretation
Claim 6 is considered to be dependent upon claim 1.
Claim 14 is considered to be dependent on claim 10.
Each of claims 15 and 16 are considered to be dependent on claim 1.
The specification supports that the same pharmaceutical composition (that produced according to the method of Example 1) is used for treating dry eye (see method of Example 2) and for treating corneal epithelia wound (See method of Example 2). Thus, the pharmaceutical compositions of claims 9 and 14 are considered identical. The recitation of intended use in the preambles only limits the compositions in so far as the composition must be suitable for application to the eye of a subject.
The claims refer to secretome of amniotic fluid stem cells. As of the effective filing date of the application there were multiple stem cell types identified within amniotic fluid, including amniotic fluid mesenchymal stem cells (AFMSCs) and c-kit+/Lin- amniotic fluid stem cells (AFSCs) (See Loukogeorgakis et al, Stem Cells, 2017, pg 1663, col. 2- pg 1664, col. 1). The instant application fails to identify from which type of stem cell the secretome is derived. Paragraph 0033 of the as-filed application recites “As used herein, the term “amniotic fluid stem cells” refers to”, no definition is given. The Examples do not provide additional information on the AFSCs, rather they only state that the AFSCs were obtained from qualified cell banks (See paragraph 0052 of the as-filed specification). Due to the lack of specificity, the claims will be given their broadest reasonable interpretation which will permit for the AFSCs of the claim to be any stem cell from amniotic fluid, thus including AFMSCs as well as c-kit+/Lin- AFSCs.
Claims 1, 6 and 9 describe the secretome of amniotic fluid stem cells by its method of production (product-by-process limitations). Production-by-process limitations are considered only in so far as the method of production effects the structure of the final product. Products of identical composition made by different methods will still read on the product as claimed. In the instant case, it is understood that culturing amniotic fluid stem cells for 24-72 hours in basal medium will result in secretion of some molecules (i.e. proteins, etc) into the culture medium. Recovering and filtering the supernatant will result in recovery of a product comprising the non-cellular fraction of the culture medium. The non-cellular fraction of the culture medium will include at least some of the secreted molecules, and may further comprise cellular debris. The exact content will depend on the gestation stage at which the amniotic fluid stem cells are harvested and the culture conditions (i.e. components of culture medium, temperature, oxygen levels, cell concentration, etc) (See Costa et al, Int’l J Mol Sci, 2021, esp Pg 19-20; Harrell, US 2021/0060084, ¶0004). The specification provides no details on the contents of secretome. As currently written, the product-by-process limitations cover an extremely broad scope of culture conditions, and thus an equally broad scope of secretome compositions.
Duplicate Claim Warning
Applicant is advised that should claim 9 be found allowable, claim 14 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof.
When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
In the case of claims 9 and 14, the preambles set forth the intended use of the compositions
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 15 and 16 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because the claim are ‘use claims.’ The claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e. results in a claim which is not a proper process under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ678 (Bd.App.1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp.131, 149 USPQ 475 (D.D.C.1966).
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.
Claims 15-16 are 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.
Claims 15 and 16 are directed to uses of the pharmaceutical compositions of claims 9 and 14, respectively. Claims 15 and 16 provide for the use of the pharmaceutical compositions, but, since the claim does not set forth any steps involved in the method/process, it is unclear what method/process applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6-8, 12 and 14-16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claims 6-8: Claim 6 depends from claim 1. Claim 6 is an improper dependent claim as it fails to further limit the method of claim 1, but rather recites a distinct method (treatment of corneal epithelia wounds). Claims 7 and 8 inherit the deficiency.
Regarding claim 12: Claim 12 recites a potential use of the composition, but fails to present any limitation which further limits the structure or composition thereof.
Regarding claim 14: Claim 14 is an improper dependent claim because it fails to further limit the composition of parent claim 12. The composition of claim 14 is identical to the composition of claim 12 (given that the specification teaches the identical compositions are suitable for treatment of dry eye and corneal epithelia wound healing).
Regarding claims 15 and 16: Each of these claims depends from claim 1, however they are improper dependent claims as both claims 15 and 16 are broader than the method of claim 15. A dependent claim must recite a further limitation of the parent claim, it may not broaden the parent claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 9-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Costa et al (Int J Mol Sci, 2021 Apr), evidenced by Nanoparticle Ultrafiltration (Millipore Sigma, 2023).
Costa et al perform comprehensive profile of secretome of human amniotic fluid stem cells (See title).
To prepare the human amniotic fluid stem cell (hAFS) secretome fractions Costa et al culture f-hAFS and p-hAFS in serum-free medium for 24 hrs under normoxic or hypoxic conditions. hAFS-conditioned medium (h-AFS-CM) were collected from each culture by centrifugation, then concentrated using Amicon Ultra-15 (Merck Millipore) ultrafiltration membranes with 3kDa selective cut-off (See Pg. 23, 4.5 Separation and Concentration of the hAFS Secretome Fractions).
Regarding claims 9, 12, and 14: The concentrated hAFS-CM is secretome of human amniotic fluid stem cells, specifically hAFS which have been cultured in basal medium (the serum-free medium contains DMEM) for 24 hrs, then the supernatant was collected via centrifugation and filtering. The water in the serum-free medium reads on a pharmaceutically acceptable carrier. The hAFS-CM is capable of being administered to the eye. Thus the recovered, concentrated hAFS-CM reads on a pharmaceutical composition as claimed.
Regarding claim 13: The concentrated hAFS-CM is a liquid. The liquid reads on an eye drop solution.
Regarding claims 10 and 11: Costa et al concentrate the hAFS-CM through use of Amicon Ultra-15 ultrafiltration membranes with 3kDa selective cut-off. The “Nanoparticle Ultrafiltration” article by Millipore Sigma evidences that ultrafiltration membranes with 3kDa selective cut-off have a nominal pore size of 0.3 nm. Thus the hAFS-CM has been filtered through a filter having a pore size of less than 0.5 µm, and less than 0.22 µm.
Claims 9 and 12-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kukemberg et al (Scientific Reports, 2021, Jan).
Kukemberg et al disclose use of amniotic fluid stem cell secretome (AFSC-S) for use in treatment following myocardial ischemia-reperfusion injury (See abstract).
Specifically, Kukemberg et al disclose generating AFSC-S by culturing AFSCs in basal MEMα in either normoxic or hypoxic conditions, and collecting medium 6-hourly between 6 and 30 hrs. The collected medium were filtered and stored prior to use. The 30 h hAFSC-S was selected for use in animal studies. The 30 h hAFSC-S was diluted with basal MEMα to standardize, then concentrated using centrifugal filter units (See Pg 11 “Generation of amniotic fluid stem cells secretome (AFSC-S)”).
Regarding claims 9 and 12: The 30 hr hAFSC-S contains the secretome of AFSCs cultured in basal medium for 30 hrs, which secretome is then recovered and filtered. The MEMα used to dilute the hAFSC-S reads on a pharmaceutically acceptable carrier. The concentrated hAFSC-S is capable of being administered to the eye, thus reads on the pharmaceutical composition as claimed.
Regarding claim 13: The concentrated hAFS-CM is a liquid. The liquid reads on an eye drop solution.
Claims 9-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by You et al (US Patent 8586540).
You et al disclose compositions for improving skin comprising the culture medium of fetal-derived mesenchymal stem cells (MSCs), specifically fetal-derived MSCs from the amniotic fluid (See col. 3, ln 20-25 and col 3, ln 43-44).
In Example 1, You et al obtain fetal-derived MSCs from amniotic fluid (See col. 8, ln 40-57).
In Example 4, You et al prepare conditioned medium from the MSCs from amniotic fluid. Specifically, You et al report seeding the MSCs into cell culture plates containing a first medium, then after 12 hours, replacing the first medium with a second medium, said second medium being DMEM/F12 serum-free conditioned medium. The MSCs are cultured in the second medium for 72 hrs. After 72 hrs the medium is centrifuged and filtered through a “0.2 syringe filter” to obtain conditioned medium (See col. 9, ln 50-col. 10, ln 14).
The filtered conditioned medium is considered to read on the claims as follows:
Regarding claim 9: The conditioned medium is considered to read on a pharmaceutical composition. Though You et al does not contemplate the conditioned medium for treatment of dye eye or corneal epithelia wound healing, these are intended uses that do not distinguish the claimed composition from that of You et al. The conditioned medium is capable of being applied to the eye of a subject (noting that it is of physical form capable of being applied to the eye and there is no express disclosure of presence of agents or components that make it unsuitable for ocular application).
The conditioned medium is generated from amniotic fluid-derived MSCs. Amniotic fluid-derived MSCs read on amniotic fluid stem cells. The conditioned medium comprises the secretome of the amniotic fluid stem cells. Specifically, the conditioned medium comprises all components secreted by the cells when cultured in basal medium (the DMEM/F12) for 72 hrs. The conditioned medium is subject to centrifugation and filtration. You et al state the conditioned medium is filtered through “0.20 syringe filter”. Official notice is taken that “0.20 syringe filter” refers to a syringe with a 0.20 µm pore size.
Regarding claims 10-11 and 14: Following the discussion of claim 9 above, the conditioned medium has been passed through a filter with a 0.20 µm pore. 0.20 µm is less than 0.5 and less than 0.22 µm.
Regarding claims 12-13: Following the discussion of claim 9 above, the conditioned medium can be applied to the eye, and thus can be considered eye drop solution, eyebath, or eye spray. You et al further disclose numerous well known pharmaceutically acceptable carriers which can be mixed with the medium, including, inter alia, water (See col. 5, ln 60- col. 6, ln 13). The combination of conditioned medium and water can be considered eye drop solution, eyebath or eye spray.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Alford (US Patent 10758571), in view of Mistry et al (US 2006/0280729), and Roubelakis et al (Stem Cells International, 2012).
Alford disclose a mesenchymal stem cell secretome (MSC-S) composition as defined at col 2, ln 55-col. 3, ln 5 and/or at col. 7, ln 1-15. The composition can further comprise an adhesive agent, such as hypromellose (See Alford col. 3, ln 61-col. 4, ln 3). Alford disclose ophthalmic solutions for topical ocular instillation comprising the MSC-S, monobasic sodium phosphate, trehalose dihydrate, mannitol, hypromellose, water and hydrochloric acid and/or sodium hydroxide to adjust pH (See Alford col. 57, ln 50-col. 58, ln 5, see col. 61, ln 14-22). Alford describes mesenchymal stem cells as having the surface marker profile CD45-/CD31-/CD73+/CD90+/CD105+/CD44+ (See Alford, col. 20, ln 3-16). Alford disclose that the MSCs can be isolated from a variety of adult tissues, including inter alia, bone marrow and amniotic fluid (See Alford, col. 34, ln 20-25, and col. 60, ln 46-49).
Alford further disclose methods of making said MSC secretome composition comprising:
Culturing MSCs in a first culture medium;
Removing the first culture media from step (i) from the MSCs,
Washing the MSCs in step (ii)
Adding a second culture media and culturing for about 1-5 days;
Harvesting the second cell culture media from step (iv) as conditioned media; and
Processing the conditioned medium from step (v) into the MSC secretome composition (See Alford col. 4, ln 4-19).
The processing step (vi) involves:
Filtering the harvested conditioned media from step (v) to remove cell particulate;
Concentrating the filtered conditioned media from step (a); and
Buffer exchanging with the formulation buffer (see Alford col. 4, ln 20-28).
The filtering step (b) involves use of, inter alia, a 0.22 µm filter (See Alford col. 4, ln 33-37).
Alford further disclose methods of using the mesenchymal stem cell secretome composition for inducing and/or promoting ocular wound healing by administering to a patient in need thereof (See Alford col. 4, ln 57-62, as well as col. 9, ln 34-51)). Alford further disclose methods of treatment if ocular conditions, including treatment of dry eye (see Alford col. 45, ln. 47-50), treatment of chemical burns to the eye (see Alford col. 47, ln 38-39) and/or treatment of corneal wounds (See Alford, col. 60, ln 38-40). The composition can be administered topically (see Alford, col. 48, ln 1-2), including topical application to the ocular surface (See Alford col. 61, ln 14-22).
The disclosure of Alford reads on the instant claims as follows: Regarding claims 1-14: Alford disclose a pharmaceutical composition appropriate for topical ocular instillation comprising MSC-S. The pharmaceutical composition reads on eye gel, eye drop solution, eyebath and eye spray. Alford teach administration of the pharmaceutical composition for inter alia, treatment of dry eye and corneal wound healing.
The manner in which the MSC-S is made is substantially similar to the method described in the current product-by-process claims. Specifically the MSCs are cultured in basal medium for 1-5 days (which substantially overlaps with 24-72 hours, it is submitted that selection of exact duration of culture is a matter of routine optimization, the duration of culture directly affects the amount of secretome released and can be manipulated with optimization of culture conditions), then filtered through a filter having a pore size of 0.22 µm. It is submitted that the resulting secretome will be identical, to the secretome produced by the process recited by the current claims.
Alford differs from the instant claims only in that Alford is generic to the type of mesenchymal stem cells used to form the MSC-S. Alford only exemplifies use of bone marrow-derived MSCs. However, Alford does teach that amniotic fluid is a source of MSCs. It would have been prima facie obvious to try amniotic fluid MSCs (which read on amniotic fluid stem cells) as the source of MSCs based on the disclosure of amniotic fluid being one of a finite number of known MSCs available in the human body (See Alford, col. 60, ln 46-49, see Mistry ¶0023). It has been held that "a person with ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense." See KSR International Co. v Teleflex, Inc. 82 USPQ2d 1385 at 1390.
There would have been a reasonable expectation that amniotic fluid MSCs (AF-MSCs) would have been as suitable as bone marrow MSCs as the MSCs for production of MSC-S of Alford because Mistry et al teach both bone marrow and amniotic fluid stem cells were known in the art to be suitable sources of secretome for treatment of ocular conditions. Mistry et al teach that MSCs, as well as conditioned medium therefrom, are suitable therapeutics for treatment of ocular conditions. Mistry et al teach the MSCs can be, inter alia, bone marrow- or amniotic fluid-derived (See Mistry ¶0023, 0066). Furthermore, AF-MSCs are CD45-/CD31-/CD73+/CD90+/CD105+/CD44+ (See Roubelakis et al, Pg 2, “2.1. Amniotic fluid stem cells”), which meets the criteria required by Alford. Furthermore, AF-MSCs were known to secrete trophic factors as required by Alford, specifically:
FGF7, TIMP-1, TIMP-2, SERPINE1, VEGF;
MCP1, IL-17, SDF-1, IL-8; and
uPA, and endostatin (See Roubelakis et al, Fig. 1).
Based on the above factors, there would have been reasonable basis to conclude that amniotic fluid MSCs would be appropriate for use as the MSCs for production of MSC-S in the method of Alford.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
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/ALLISON M FOX/ Primary Examiner, Art Unit 1633
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