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 instant application is in response to the papers filed on December 2, 2024, of which claims 1-20 were filed, and are currently pending. Therefore, claims 1-20 are currently under examination to which the following grounds of rejection are applicable.
Priority
The instant application claims foreign priority 35 U.S.C. 119(a)-(d) to European Patent Application No. EP 22177263.5 filed on June 3, 2022, and PCT Application No. PCT/EP2023/064627 filed on June 1, 2023. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Thus, the earliest possible priority for the instant application is June 3, 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on December 2, 2024, April 1, 2025, and April 2, 2025 were filed. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
In the instant case, the abstract is objected to for including a citation therein rendering the language too formal as extensive details such as citations should not be included. Secondly, the inclusion of citations in an abstract should be avoided as it is meant to stand alone without the need to locate and possess a secondary material for understanding of the instant disclosure.
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the applicant’s use.
Arrangement of the Specification:
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
The Specification is missing the appropriate section headers, section content, and/or layout related to these sections as outlined above. For example, the Specification is missing section (b) CROSS-REFERENCE TO RELATED APPLICATIONS, and does not include other appropriate section headers as recited above, e.g. uses “Legends” where “Drawings” is the standard language.
Incorporation by Reference:
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or an official IDS, they have not been considered.
Claim Objections
Claim 6 is objected to because the recited abbreviations: “ACVRL1, BMPR2, ENG, CAV1, EDN1, SMAD4, SMAD9, AGTR1, BMPR1B, EDNRA, EIF2AK4, KCNA5, KCNK3, NOS2, NOTCH3, SERPINE1, SIRT3, SOX17, TBX4, THBS1, TOPBP1 and TRPC6,” should be spelled out at the first encounter in the claims.
Claim 8 is objected to because the recited abbreviations: “LRP1, APOE, MAPK11, FGF16, and LRP8,” should be spelled out at the first encounter in the claims.
Claim 10 is objected to for incorrectly spelling “concentrated” in line 2.
Claim 12 is objected to for the recitation of “intracoronaryly” because the proper spelling appears to be “intracoronary”.
Claim 16 is objected to because the recited abbreviation: “ACVRL1,” should be spelled out at the first encounter in the claims.
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 1-20 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.
Claim 1 is directed to a “use” claim. This claim is indefinite since the claim does not set forth any steps involved in the method/process of using and due to the claim being unclear what method/process applicant is intending to encompass. Additionally, because this claim does not set forth any steps involved in the process, it results in an improper definition of a process, i.e., results in a claim which is not a proper process claim. For the sake of compact prosecution, the Examiner has interpreted claim 1, to a composition of a human umbilical cord mesenchymal stem cell-conditioned medium. If Applicants do not wish for this claim to be interpreted as a composition, Applicants are invited to amend the claims, at which point, the Examiner will determine if the amended claims fall within the elected group.
Claim 17 is indefinite for using the units “100 ng PGE2/mg protein” and “18 ng PGF2a/mg protein”, the denominator of “mg protein” is not clear. It appears the Applicant intended to use “mL of the conditioned medium” as seen in claim 13.
Claim 19 is indefinite for reciting “a dose of 100 to 500 ml” as it is unclear if the dosage is referring to the same dosage introduced in claim 13 in relation to the conditioned medium or rather a different dosage, and if the latter the composition is not clear as it is not recited with the dosage.
Claims 2-16, 18, and 20 are rejected by dependency to the rejected claims, and for not absolving the indefinite issues set forth therein.
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 1-7, 9-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural product without significantly more.
Applicant is directed to the 2019 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on 1/07/2019, which is found at: https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf; and the October 2019 Update: Subject Matter Eligibility, which is found at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf.
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
Step 1: Regarding claim 1, the claim is directed to a human umbilical cord mesenchymal stem cell-conditioned medium for use in treatment of a chronic heart-lung and vascular disease in a human subject. The claim is directed to the statutory category of a composition of matter. It is noted the claim is rejected under 35 USC 112(b) for the inclusion of “use for” as described above, but regardless the claim is directed to a statutory category. Accordingly, the requirements of Step 1 are met.
Step 2A, Prong One: Regarding Step 2A Prong One, claim 1 is directed to a natural phenomenon (product of nature) based on the lack of elements that would differentiate the conditioned media from a non-natural product, e.g. Wharton’s Jelly (WJ). The dependent claims 7-11, 17-18 recite structural limitations of the conditioned medium, yet these limitations do not change this classification. Claims 7-9, 17-18 recite the conditioned medium comprising select proteins, lipids, and extracellular vesicles that are naturally occurring, and furthermore claims 10, 11 recite limitations that do not change the composition from the naturally occurring composition.
Step 2A, Prong Two: The judicial exception is not integrated into a practical application based on the claims not reciting additional elements of the composition that would integrate into such composition into a practical application as the structural limitations currently recited are not different than naturally occurring compositions, e.g. WJ. The recitation of “for use in treatment of a chronic heart-lung and vascular disease in a human subject” is considered intended usage which does not add a meaningful limitation to the composition as this is nothing more than an attempt to generally link the product of nature to a particular technological environment. Limitations that amount to merely indicating a field of use or technological environment in which to apply a judicial exception do not amount to significantly more than the exception itself, and cannot integrate a judicial exception into a practical application. See MPEP 2106.05(h).
Step 2B: The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As stated above (see Step 2A prong one above), there are no additional elements recited other intended usage. In reference to the limitation of “conditioned medium,” the label characterization of “conditioned medium” is not sufficient to differentiate itself from the naturally occurring compositions such as Wharton’s Jelly of which human umbilical cord mesenchymal stem cells are located and derived. The conditioned medium is intended to replicate the intracellular fluid from which these cells are derived, and secondly there is no indication that the claimed medium contains components that are not naturally occurring, and are not found normally in combination.
Judicial Exception – Conclusion: Therefore, the claims are directed to a natural product without significantly more that is not integrated into a practical application, does not include elements that amount to significantly more than the natural product, and does not qualify as patent eligible subject matter under 35 U.S.C. § 101.
Claim Rejections - 35 USC § 102
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 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 1-6, 11-16, and 19-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pierro et al. ("Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia." Thorax 68.5 (2013): 475-484).
Regarding claim 1, Pierro teaches a human umbilical cord mesenchymal stem cell-conditioned medium for use in treating and preventing lung injuries such as Bronchopulmonary dysplasia (BPD) (“In order to investigate the mechanisms underlying the beneficial effects and with the perspective of a ‘pharmaceutical’ cell-based therapy, we also tested the therapeutic potential of conditioned media (CdM) from cord-derived PCs and cord blood-derived MSCs.” (p 34, col 1); “PC and MSC CdM were effective in preventing pulmonary arterial wall remodelling (figure 6A,B) and right ventricular hypertrophy (figure 6C), two structural features of pulmonary hypertension. Similar to whole cell therapy, therapeutic administration of PC and MSC CdM (from P14 to P28 assessed in 24 animals) after established lung injury improved alveolar architecture (figure 7A–C) and lung function (figure 7D). (p 35, col 2).
Regarding claim 11, Pierro teaches wherein the conditioned medium is serum-free medium harvested from a subconfluent culture of mesenchymal stem cells after 12 to 60 hours of culture (“Cells were grown in 75t flask up to 90% confluence (MSC 1.500.000 cells/ f[l]ask, PCs 1.000.000 cells/flask). Then cells were rinsed 3 times with PBS and serum free media was added. After 24 hours the supernatant was harvested.” (Supplemental p 2, par 1).
Regarding claims 2-6, 12-16, and 19-20, these claims recite limitations pertaining to the intended usage of the composition which is recited in claim 1 as use in treatment of a chronic heart-lung and vascular disease in a human subject. MPEP 2114 states, “A claim containing a "recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus" if the prior art apparatus teaches all the structural limitations of the claim. Ex parte Masham, 2 USPQ2d 1647 (Bd. Pat. App. & Inter. 1987).” Therefore, the intended use and limitations pertaining thereto are not given any patentable as they do not clearly impart any structural differences from the prior art.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7, 9-16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Pierro et al. ("Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia." Thorax 68.5 (2013): 475-484) as applied to claims 1-6, 11-16, and 19-20 above, and further in view of Bogatcheva et al. (Biochemistry (Moscow) 84.11 (2019): 1375-1389).
The teachings of Pierro are discussed supra.
Regarding claim 7, Pierro teaches a human umbilical cord mesenchymal stem cell-conditioned medium for use in treatment of a chronic heart-lung and vascular disease in a human subject, but does not teach such composition as comprising prostaglandin 2 (PGE2), wherein the conditioned medium optionally further comprises PGF2α.
Bogatcheva teaches conditioned media from MSCs, including umbilical cord MSCs (UC-MSCs), comprise PGE2, and further states the levels of PGE2 in CM may be used to predict therapeutic efficacy (p 1383, col 2; Table 4).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have modified conditioned medium taught by Pierro et al. by stating the conditioned medium derived from UC-MSC comprises PGE2 (as taught by Bogatcheva et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. The inclusion of PGE2 in the CM would have led to predictable results with a reasonable expectation of success because Bogatcheva teaches MSC secrete the lipid, and is found in CM, and therefore there is reasonable expectation that the CM derived from UC-MSC as taught by Pierro would also likely have PGE2 as some concentration.
Regarding claim 9, Pierro does not teach the CM as containing extracellular vesicles (EVs).
Bogatcheva further describes MSCs secrete extracellular vesicles (EVs) to target cancer cells, and states “two types of CM products are being developed with the purpose of therapeutic/cosmeceutical application, namely, CM concentrates and EV isolates. The first type is not devoid of EVs, whereas the second type is deficient in the majority of soluble factors not associated with EVs.” (p 1376, col 1).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have modified conditioned medium taught by Pierro et al. by stating the conditioned medium derived from UC-MSC comprises EVs (as taught by Bogatcheva et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. The inclusion of EVs in the CM would have led to predictable results with a reasonable expectation of success because Bogatcheva teaches MSC secrete EVs to target cells, and therefore there is reasonable expectation that the CM derived from UC-MSC as taught by Pierro would also likely have EVs.
Regarding claim 10, Pierro does not teach the conditioned medium as not concentratred via filtration, but rather using ultrafiltration (Supplemental p 2, par 1).
Bogatcheva describes in routine preparation the CM can be treated with filtration to be concentrated or by using other methods, or rather left nonconcentrated (p 1377, col 1).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have modified conditioned medium taught by Pierro et al. by stating the conditioned medium derived from UC-MSC is not filtered (as taught by Bogatcheva et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. The option to not use filtration is clearly described by Bogatcheva when used in different disease models wherein the effects observed are characterized (Table 1); and states if concentrated there are other methods outside of filtration, e.g. polyethylene glycol precipitation, ExoQuick TC (proprietary polymer) precipitation (p 1377, col 1). Therefore, it would obvious to not use filtration on the CM taught by Pierro dependent on the intended use of the composition, the preparation methods & technologies accessible, and dependent on the therapeutic product consisting essentially of EVs or a mix of EVs with the conditioned medium which is compared by Bogatcheva as seen in Table 3.
Regarding claim 18, that recites wherein the conditioned medium does not essentially consist of extracellular vesicles, the Applicant describes in the Specification paragraph 0040:
In other prior art documents, isolated extracellular vesicles (EVs) from MSC-conditioned medium have been used for treatment of chronic heart-lung and vascular diseases in animal models. This is not the case in the context of the present invention. The conditioned medium of the present invention does not essentially or purely consist of isolated extracellular vesicles. Rather, it comprises both extracellular vesicles and components that are not comprised in the extracellular vesicles, e.g., free PGE2. Preferably, the extracellular vesicles are not enriched in the conditioned medium. For example, no ultracentrifugation is carried out to isolate or enrich extracellular vesicles.
Therefore, Pierro and Bogatcheva teach this limitation as they both teach a culture medium that contains EVs and components that are not comprised in the extracellular vesicles by not teaching only isolated EVs.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Pierro et al. (Thorax 68.5 (2013): 475-484) in view of Bogatcheva et al. (Biochemistry (Moscow) 84.11 (2019): 1375-1389) as applied to claims 1-7, 9-16 and 18-20, further in view of Santos et al. (Prostaglandins, Leukotrienes and Essential Fatty Acids 163 (2020): 102210).
The teachings of Pierro and Bogatcheva are discussed supra.
Regarding claim 17, Pierro teaches a human umbilical cord mesenchymal stem cell-conditioned medium for use in treatment of a chronic heart-lung and vascular disease in a human subject, but does not teach such composition as comprising prostaglandin 2 (PGE2), wherein the conditioned medium optionally further comprises PGF2α. Bogatcheva teaches conditioned media from MSCs, including umbilical cord MSCs (UC-MSCs), comprise PGE2, and further states the levels of PGE2 in CM may be used to predict therapeutic efficacy (p 1383, col 2; Table 4).
Pierro in view of Bogatcheva do not teach the CM as further comprising PGF2α, and at a select concentration. The concentration is rejected under 35 USC 112(b) above for the units not being clear, and therefore at this time the concentration limitations cannot be examined accordingly.
Santos teaches PGE2 has anti-inflammatory and immunomodulatory effects mediated by MSC, and furthermore describes that MSCs synthesize PGF2α. Lastly, MSC conditioned media from cells stimulated with PGF2α increase the macrophage production of IL-10, which is a “well-known cytokine able to exert a protective effect against inflammation due to generalized downregulation of proinflammatory cytokines such as IL-1, TNF-α, and IL-6” (Fig. 4A; p 6, col 2; abstract).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have modified conditioned medium taught by Pierro et al. in view Bogatcheva by stating the conditioned medium derived from UC-MSC further comprises PGF2α (as taught by Santos et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. The inclusion of PGF2α in the CM would have led to predictable results with a reasonable expectation of success because Santos teaches MSCs secrete this particular prostaglandin in addition to PGE2 which have effects on cytokine levels, e.g. IL-10, and therefore there is reasonable expectation that the CM derived from UC-MSC as taught by Pierro in view of Bogatcheva would also both prostaglandins found therein based on MSCs being described as synthesizing these lipids.
Conclusion
Claims 1-20 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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