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 .
Response to Amendment
The amendment filed 12/19/2025, amending claim(s) 74, 77, 79-82, 84-87, and 91, cancelling claim(s) 75, 76, 83 and 90, and newly adding claim(s) 94 and 95 is acknowledged.
Claims 74, 77-82, 84-89, and 91-95 are pending and under examination.
Specification
The corrected specification filed 12/19/2025, which corrects the typographical error of “decreased” rather than reciting “increased” starting at page 27 line 21 is accepted. Support for this correction is found in Figure 3 and its description on page 6, lines 1-10 of the specification.
Priority
Applicant’s claim for the benefit of a prior-filed foreign application EP20173592.5 filed 05/07/2020, and PCT/EP2021/062111 filed 05/07/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, foreign application EP20173592.5 filed 05/07/2020 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
EP20173592.5 fails to provide support for the limitation of “said therapeutically effective amount of a composition comprising integrin alpha10-selected MSCs increases coagulation time, which is now required in base claims 74 and 91.
Therefore, the claims of the instant case are entitled to the priority date of PCT/EP2021/062111 filed 05/07/2021.
Information Disclosure Statement
The information disclosure statements filed 12/19/2025 and 02/05/2026 fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Claim Rejections - 35 USC § 112(a)- Written Description - Modified, necessitated by amendment
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 74, 77-82, 84-89, and 91-95 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 74 and 91 recite “wherein said therapeutically effective amount of a composition comprising integrin a10-selected MSCs increases coagulation time”. The recitation of “a therapeutically effective amount” in the claims denotes that not all amounts of the therapeutic agent are effective at treating a disease or condition. What is the objective amount that is not ‘effective’, as opposed to the objective amount that is necessarily and predictably ‘effective’? How does an artisan determine what would be an effective amount to increase coagulation time?
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
A search of the specification of ‘effective’ returned no results other than repeated recitations of “the method comprising administering a therapeutically effective amount of a composition comprising integrin a10-selected Mesenchymal Stem Cells (MSCs)”.
Additionally, the recitation of “wherein said therapeutically effective amount of a composition comprising integrin a10-selected MSCs increases coagulation time” is recited at a high level of generality and defines the term ‘therapeutically effective amount” functionally rather than structurally. However, the claims also recite “wherein at least 60% of the MSCs in the composition express integrin alpha10”. As written, the claims indicate that the composition comprising 60% of MSCs expressing integrin alpha10 (structure) does not necessarily also increase coagulation time (function). The specification fails to provide any guidance for the ordinary artisan to carry out the claimed method with 60% of MSCs expressing integrin alpha10, but not have an amount of MSCs increase coagulation time, for example.
Further, the specification offers little guidance on the vastly broad other variables/parameters that determining a “therapeutically effective amount” is dependent upon.
For example, page 17 of the specification broadly recites:
“In some embodiments of the present disclosure, the composition comprising the integrin alpha10-selected MSCs is administered into the lung or airways. In some embodiments of the present disclosure, wherein the composition comprising the integrin alpha10-selected MSCs is administered via injection. The person skilled in the art will know of other ways known in the art for administration of integrin alpha10-selected MSCs. In some embodiments of the present disclosure, the composition comprising the integrin alpha10-selected MSCs is administered parenterally. Accordingly, the composition comprising integrin alpha10-selected MSCs for use according to the present disclosure may be administered topically to cross any mucosal membrane of an animal to which the integrin alpha10-selected MSCs is to be given. In some embodiments of the present disclosure, the composition comprising the integrin alpha10-selected MSCs is administered via intravenous injection, intramuscular injection and/or intratracheal injection, or any combination thereof”.
The specification does not recite any dosing schedule.
Additionally, independent claim 91 fails to recite what dose is required to achieve the functional limitation(s) of: preventing blood clotting; promoting hemodynamic stability; reducing the need for inotropic support; improving oxygenation capacity; preventing tissue damage; reverting tissue damage; reducing neutrophil counts; increasing lymphocyte counts; decreasing proinflammatory cytokines; and increasing interferon-a. The breadth of the claims encompass any dose of the composition. The claims fail to recite, and the specification fails to disclose what structure (e.g., dose, amount of MSCs) are necessary and sufficient to achieve preventing blood clotting; promoting hemodynamic stability; reducing the need for inotropic support; improving oxygenation capacity; preventing tissue damage (including lung tissue damage, damage of the interstitial tissue, damage of the alveolar septa, damage of the airways, damage of the vasculature, and/or damage of the nervous system as recited in claim 92); reverting tissue damage; reducing neutrophil counts; increasing lymphocyte counts; decreasing proinflammatory cytokines; and increasing interferon-a.
Examples 2 and 3 recite intravenously administering 5 million MSCs/kg, and found improved hemodynamics, lung oxygenation, increased blood clot formation, lowered neutrophil levels, increased lymphocyte levels, lowered IL-12, IL-1beta, and IL-6, and elevated IFN-alpha. Is this the minimal dosage required to achieve these results, which are distinct from other claimed outcomes such as preventing tissue damage and preventing blood clotting (as decreasing blood clot time formation is not the same as preventing a blood clot from forming in the first place)?
Claims 84 and 85 (dependent upon claim 74) further limits the MSCs to be administered via injection and parentally, respectively.
The specification, including the recitations above, do not provide any guidance or teachings on what amount(s) are ‘effective’ for treating a vastly broad genus of diseases and conditions in a vast number of subjects.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement - Modified, necessitated by amendment
Claims 74, 77-82, 84-89, and 91-95 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method for treating acute ARDS in a mammalian subject, the method comprising intravenously administering autologous or allogenic integrin alpha10-selected MSCs at a dose of 5 million MSCs/kg to the subject, wherein at least 60% of the MSCs in the composition express integrin alpha10,
does not reasonably provide enablement for
a method for treatment of any ARDS-associated disorder in a mammalian subject, the method comprising administering a therapeutically effective amount of a composition comprising integrin a10-selected Mesenchymal Stem Cells (MSCs) to an individual in need thereof, wherein said therapeutically effective amount of a composition comprising integrin a10-selected MSCs increases coagulation time.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
Nature of Invention: The claims are directed to a method for treatment of acute respiratory distress syndrome (ARDS) and/or associated disorders, and a method to ameliorate, or treat a symptom of ARDS (as listed in claim 91) by administering integrin alpha10-selected MSCs.
Breadth of Claims: The Examiner incorporates herein the analysis discussed above in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
The claims are directed to methods of treated ARDS and related disorders.
The claims are broad for reasonably encompassing a large genus of disorders.
The disorder may be cytokine release syndrome (CRS), cytokine storm syndrome (CSS), multisystem inflammatory syndrome associated with COVID-19, or respiratory distress syndrome of newborns, ARDS, cytokine mediated ARDS, ARDS/Respiratory distress syndrome of newborns, ARDS resulting from trauma, ARDS caused by viral or bacterial infection, ARDS from sepsis, or ARDS resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) / COVID-19 infection (claims 77 and 95).
The subject may be human, or a horse, pony, ox, donkey, mule, camelid, cat, dog, pig, or cow (claims 89 and 94).
The MSCs may be administered via injection. The MSCs may be administered parentally (claims 84 and 85).
The treatment may be directed to tissue damaged and decreasing proinflammatory cytokines (claims 92 and 93).
Specific Guidance of the Specification/Working Examples: The Examiner incorporates herein the analysis discussed above in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
The specification fails to provide any evidence that the method as written can be used to treat the broadly claimed genus of “ARDS and/or associated disorders”.
Example 1 discloses isolating MSCs from human or animal adipose tissue.
Example 2 discloses inducing ARDS in twelve pigs by administering diluted LPS from gram-negative E. coli via endotracheal (ET) installation and the pulmonary artery. Hemodynamic parameters, blood gases, and blood clotting time were used to confirm the porcine ARDS model. Pigs were intravenously given 5 million MSC/kg. Results included significantly less norepinephrine administered, an elevated oxygenation capacity, a decrease in blood clot time, and “less damage to the lung tissue and much better-preserved lung structure” in the MSC group compared to controls. However, it is unclear from the specification and Figure 4 what constitutes a “much better-preserved lung structure” or “preserv[ing] integrity of the lung tissue structure”.
Example 3 studied blood samples from MSC-treated pigs. Figure 5 shows decreased neutrophil counts and increased lymphocyte counts in MSC-treated pigs. Figure 6 shows lower concentrations of IL-12, IL-1beta, and IL-6 in blood plasma of MSC-treated pigs, and elevated IFN-alpha levels.
These examples show a select number of symptoms of an induced model of ARDS being treated (e.g., decreased blood clot time). The examples do not show all the symptoms of ARDS as claimed in claim 91 being ameliorated or treated. The examples also do not show any other diseases or disorders of the respiratory system being treated, nor trauma or the treatment or promotion of an organ or tissue transplant of the respiratory tract. Further, none of these examples demonstrate preventing tissue damage, as recited in claims 91 and 92, as “less damage” is not the same as “delaying or stopping onset” (e.g., as discussed in Example 2).
The teachings of the above specification are not sufficient to enable the entire scope of the claims because, while the specification teaches the administration of autologous or allogenic integrin alpha10-selected MSCs in a porcine model of ARDS, the specification fails to teach the xenogeneic administration of such cells. Further, the specification only teaches the administration of the MSCs via intravenous injection. Lastly, while the specification provides some evidence for the clinical benefit of integrin alpha10-selected MSCs for the treatment of ARDS, it fails to teach that such cells are beneficial for associated disorders.
State of the Art: The Examiner incorporates herein the analysis discussed above in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
The art teaches that MSCs hold great therapeutic potential for the treatment of respiratory diseases, including ARDS.
Zheng, Guoping, et al. "Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study." Respiratory research 15.1 (2014): 39. (NPL #11 of IDS) is considered relevant prior art for studying the clinical effects of MSCs in ARDS. Adult human patients with ARDS received one intravenous dose of 1 x 10^6 allogenic adipose-derived MSCs/kg of body weight (or saline for the placebo group). There were no infusion toxicities or serious adverse events related to MSCs administration and there were no significant differences in the overall number of adverse events between the two groups. Length of hospital stay, ventilator-free days and ICU-free days at day 28 after treatment were similar. There were no changes in biomarkers examined in the placebo group. In the MSCs group, the changes in IL-8 levels were not significant. The IL-6 levels at day 5 showed a trend towards lower levels as compared with day 0, but this trend was not statistically significant (p = 0.06). Zheng teaches that administration of allogeneic adipose-derived MSCs appears to be safe and feasible in the treatment of ARDS. However, the clinical effect with the doses of MSCs used is weak, and further optimization of this strategy is required (Abstract).
Zheng differs from the instant case in Zheng is silent on the proportion of MSCs administered being integrin alpha10-positive. However, the MSCs of Zheng and the MSCs used in the working examples both originated from adipose tissue, and both identified MSCs by the presence of CD73, CD90, and CD105, and the negative expression of CD34, CD45 and HLA-DR (pg. 3, “Characterization of MSC products”; pg. 5, “Adipose-derived MSCs”- Zheng; Example 1, pg. 25 of specification- instant case). Since both Zheng and the instant case teach culturing adipose-derived MSCs (pg. 14 of the specification notes “a skilled person in the art will know that several methods for selecting, and thereby enriching cells, can be used”), one of skill in the art would come to the conclusion that the cells share the same characteristics (as demonstrated by the flow cytometry results) and express the same genes, including integrin alpha10.
Han, Jibin, Yanmin Li, and Yuanyuan Li. "Strategies to enhance mesenchymal stem cell‐based therapies for acute respiratory distress syndrome." Stem cells international 2019.1 (2019): 5432134. (NPL #12 in IDS) is considered relevant prior art for reviewing MSC-based therapies for ARDS. Han teaches that many studies show that the level of injected MSCs that differentiate into tissue-appropriate phenotypes is very low (pg. 2, “2. Mechanisms of MSCs in Treating ARDS”, col 1). Other characteristics that may impact therapeutic outcomes include MSCs gradually losing their initial morphology and multiple differentiation ability over time, long-term culturing resulting in abnormal changes to DNA, RNA, and protein in MSCs, and the chemokine receptors and paracrine cytokines expressed by aged MSCs being markedly decreased, which in turn attenuates MSCs’ migration capacity and pleiotropic properties (pg. 8, “24. Other Strategies to Optimize MSC Therapy”).
Han reviews completed clinical studies at the time of publication regarding the treatment of ARDS with MSCs. Doses of MSCs in the studies varied, from 1 x 10^6 cells/kg to 10 x 10^6 cells/kg, and clinical results across studies were also mixed (Table 1). Han summarizes that MSC-based therapy offers great promise, but the low mobilization of MSCs to the sites of injury and poor survival of transplanted MSCs in the harsh microenvironment are obstacles faced by clinical translation (pg. 9, “25. Conclusion).
Wilson, Jennifer G., et al. "Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial." The Lancet Respiratory Medicine 3.1 (2015): 24-32. (NPL #22 of IDS) conducted a phase one clinical trial comprising administering three different doses of MSCs to human patients (low= 1 million cells/kg; intermediate= 5 million cells/kg; high= 10 million cells/kg) (Abstract). The MSCs were allogeneic and bone marrow-derived human MSCs (pg. 4, “Source and preparation of MSCs”). For the trials, MSCs were infused via gravity over approximately 60-80 minutes, with the infusion rate controlled by the investigator based on droplet count (pg. 5, “Study procedures”). IL-6, IL-8, RAGE, and Ang-2 levels in patient plasma at baseline, six hours, day one, and day three were measured, no significant differences in the magnitude of decline among groups for any of the biomarkers (pg. 8, “Plasma Biomarker Profiles”; Table 7).
Page 18 of the instant specification notes that the integrin alpha10-selected MSCs may be derived from bone marrow. The claims and working examples of the instant specification do not specifically detail the culturing conditions for the MSCs. Page 15 of the instant specification teaches that in some embodiments of the present disclosure, the MSCs are cultured in a culture media comprising factors such as mammalian serum, FGF-2, platelet lysate and/or platelet lysate components, and TGF3 alone or in various combinations, and that the media may be serum-free. The MSCs of Wilson were resuspended after cryopreservation in Plasmalyte-A, a serum-free medium. Wilson notes different findings than those reported above in Zheng, pointing out the MSCs of Zheng were re-culture in the patient’s own serum. The teachings of Wilson indicate the importance of the components of the culturing media of the MSCs and clinical outcomes.
In summary, the prior art teaches the therapeutic potential of MSC-based therapies and treating ARDS. However, the efficacy of MSCs across different modes of administration, dosage, etc. is still unpredictable and has challenges to overcome. As such, the state of the art fails to teach the administration of MSCs derived from any species to any mammal via any method of administration, and also fails to teach preventing symptoms of ARDS (such as preventing tissue damage as recited in claim 92) and treating any disease or trauma involving the respiratory system.
Amount of Experimentation: The Examiner incorporates herein the analysis discussed above in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
In order to validate a method for treatment of ARDS and associated disorders, more studies are needed that demonstrate the prevention, alleviation, reduction, elimination, etc. of a symptom of the large genus of disorders.
The instant portion of the invention, as claimed, falls under the "germ of an idea" concept defined by the CAFC. The court has stated that "patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be workable". The court continues to say that "tossing out the mere germ of an idea does not constitute an enabling disclosure" and that "the specification, not knowledge in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement". (See Genentech Inc v. Novo Nordisk A/S 42 USPQ2d 1001, at 1005). The claimed methods of nucleic acid molecules encoding a genus of structurally undisclosed and variable genus of structurally and functionally different sequences to necessarily and predictably sufficiently function as regulatory elements, constitutes such a "germ of an idea". The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
Since the quantity of experimentation required to practice the invention as claimed is undetermined, one of skill in the art would have been unable to practice the invention without engaging in undue trial and error experimentation as presented in the specification over the scope
claimed.
Thus, the quantity of necessary experimentation to make or use the invention as claimed,
based upon what is known in the art and what has been disclosed in the specification, will create
an undue burden for a person of ordinary skill in the art to necessarily and predictably use the
claimed method comprising the generically recited integrin alpha10-selected MSCs that are capable of treating the broad genus of ARDS and associated disorders in a mammal.
In conclusion, the specification fails to provide any guidance as to how an artisan would
have dealt with the art-recognized limitations of the claimed method commensurate with the
scope of the claimed invention.
Claim Rejections - 35 USC § 112(b) – Modified, necessitated by amendment
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 74, 77-82, 84-89, and 91-95 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 74 and 91 recite the term “effective amount”. The phrase “effective amount” denote(s) that there is an amount of the pharmaceutical composition comprising that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In re Fredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject(s), human or non-human animal, to be treated [parameter 1];
the structure(s)/function(s) of the therapeutic agent(s) [parameter 2];
the administration route(s) [parameter 3];
the dosage(s) administered [parameter 4];
the disease/disorder/condition(s) to be treated [parameter 5]; and
the phenotypic response(s) to be achieved [parameter 6].
The recitation of “wherein said therapeutically effective amount of a composition comprising integrin a10-selected MSCs increases coagulation time” still does not structurally limit the claim language, and instead tries to further limit “therapeutically effective amount” by a functional result that is also variable. What is the increased coagulation time in reference to? The same subject prior to administration? A different subject not receiving treatment?
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
Additionally, it is unclear whether 60% of the MSCs in the composition expressing integrin alpha10 is considered a “therapeutically effective amount”, or if a different amount of integrin alpha10-expressing MSCs is required to fulfill the limitation of “wherein said therapeutically effective amount of a composition comprising integrin a10-selected MSCs increases coagulation time”. It would be remedial to clarify the structure (e.g., amount of MSCs expressing integrin alpha10) is required to increase coagulation time. For examination purposes, 60% of MSCs expressing integrin alpha10 in the composition is interpreted to read on the required “therapeutically effective amount”.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 103 – Modified, necessitated by amendment
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.
Claim(s) 74-85, 87, 89, and 91-95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (Zheng, Guoping, et al. "Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study." Respiratory research 15.1 (2014): 39.), in further view of Varas et al. (Varas, Laura, et al. "α 10 integrin expression is up-regulated on fibroblast growth factor-2-treated mesenchymal stem cells with improved chondrogenic differentiation potential." Stem cells and development 16.6 (2007): 965-978.) (NPL #19 of IDS), as evidenced by Gopar-Cuevas et al. (Gopar-Cuevas, Yareth, et al. ‘Chondrocyte Turnover in Lung Cartilage’. Cartilage Repair and Regeneration, InTech, 14 Feb. 2018. Crossref, https://doi.org/10.5772/intechopen.70860.).
Regarding claims 74, 79, 80, 87, 89, 91, 94, and 95, Zheng et al. teaches the treatment of ARDS (claims 91, 95) by administering allogeneic adipose-derived MSCs to human (claims 89 and 94) subjects (Abstract).
Zheng et al. is silent on the proportion of MSCs administered being integrin alpha10-selected MSCs. However, as discussed above, the MSCs of Zheng et al. and the MSCs used in the working examples both originated from adipose tissue, and both identified MSCs by the presence of CD73, CD90, and CD105 (claim 80), and the negative expression of CD34, CD45 and HLA-DR (claim 79) (pg. 3, “Characterization of MSC products”; pg. 5, “Adipose-derived MSCs”- Zheng; Example 1, pg. 25 of specification- instant case). Additionally, the MSCs of Zheng were cultured in DMEM, FBS, EGF, and FGF prior to cryopreservation, and after thawing, cultured in the patient’s own serum prior to administration (i.e., mammalian serum) (pg. 3, “MSCs expansion”). While the instant claims and working examples of the instant specification fail to teach the culture media composition of the MSCs used, page 15 of the instant specification discloses that in some embodiments, the MSCs may be cultured in media comprising mammalian serum and FGF-2.
An Artisan, interested in integrin alpha10-expressing MSCs, would be aware of Varas et al. for teaching the upregulation of integrin alpha10 in MSCs and the resulting characteristics/functions.
Varas et al. teaches increased expression of integrin alpha10 when MSCs are cultured in chondrogenic medium or treated with FGF-2 (Abstract). Varas et al. notes that MSCs express a variety of different integrins that are involved in cellular events, such as proliferation, differentiation, adhesion, and migration, with alpha10 being the main collagen-binding integrin on chondrocytes in cartilage, but is also found on heart valves and tendon (pg. 966, col 1, para 3).
Additionally, Varas teaches the value of integrin-alpha10 as a marker for MSCs in a therapeutic context, stating “Markers defining the differentiation state or differentiation potential of MSCs are important, e.g., when optimizing cultivation systems and to characterize high-quality MSCs used for therapy. Presently, to determine the level of differentiation, the isolated cells have to be tested in time-consuming assays for their differentiation capacity into the osteogenic, adipogenic and chondrogenic lineages. We believe that antibodies recognizing 10- as well as 11-integrins can be of great value in the field of MSC research.” (pg. 976, col 2, para 2).
Since both Zheng et al. and the instant case teach culturing adipose-derived MSCs in the same manner, one of ordinary skill in the art would conclude that the cells share the same characteristics (as demonstrated by the flow cytometry results) and express the same genes, including integrin alpha10. Further, it would be obvious to an artisan of ordinary skill to obtain a population of at least 60% (or 65%- claim 78) MSCs expressing integrin alpha10 using known techniques/methods in the art, such as FACs (e.g., selected with an anti-integrin alpha10 antibody- claim 87), as evidenced by Varas et al. One would be motivated to select for integrin alpha10 MSCs because as taught by Varas et al., integrin alpha10 is a novel cell surface marker for MSCs with high proliferative activity and sustained chondrogenic potential (chondrocytes form cartilage tissue, which is found in the respiratory system, as evidenced by Gopar-Cuevas et al. (Gopar-Cuevas discusses nestin-expressing MSCs, but the teachings of lung chondrocytes in maintaining homeostasis and/or repairing damaged tissue are still relevant- see pg. 34, “5. Cell renewal in lung cartilage”, for example) (pg. 974, col 1-2 of Varas et al.).
Regarding claims 81, 82, 84, and 85, Zheng et al. teaches peripheral intravenous infusion of the cells suspended in saline (i.e., a pharmaceutically acceptable excipient) (i.e., resulting in MSCs being administered (delivered to) the lungs or airways, as evidenced in Figure 2) (pg. 3, “Study design and treatment”).
Regarding claim 91, the Examiner notes that the recitation of “wherein the symptoms are selected from: preventing blood clotting; promoting hemodynamic stability; reducing the need for inotropic support; improving oxygenation capacity; preventing tissue damage; reverting tissue damage; reducing neutrophil counts; increasing lymphocyte counts; decreasing proinflammatory cytokines; and increasing interferon-a” does not recite any additional active method steps, but simply state a characterization or conclusion of the results of the active method steps positively recited. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
The teachings of Zheng and Varas discussed above are applied to claims 91-93. Zheng teaches a decrease (i.e., trend toward lower levels) in IL-6 following administration of MSCs (Abstract).
Claim(s) 74, 78-82, and 84-88 is/are rejected under 35 U.S.C. 103 as being unpatentable over Watanabe et al. (Watanabe, Hironosuke, et al. "Adipose-derived mesenchymal stem cells attenuate rejection in a rat lung transplantation model." journal of surgical research 227 (2018): 17-27.) in further view of Varas et al., as evidenced by Gopar-Cuevas et al.
Regarding claims 74, 81, 84, 85, and 86, Watanabe et al. teaches intravenously administering (i.e., administered into the lung/airways- claim 81, via injection- claim 84, parenterally- claim 85) each rat’s own adipose-derived mesenchymal stem cells (ADMSCs) immediately after orthotopic left lung transplantation (i.e., administered during surgery in connection with lung transplantation- claim 86) in order to treat/promote transplantation of an organ or tissue of the respiratory tract (Abstract).
Watanabe et al. is silent on the proportion of MSCs administered being integrin alpha10-selected MSCs. However, the MSCs of Watanabe et al. and the MSCs used in the working examples both originated from adipose tissue, and both identified MSCs by the presence of CD73 and CD90 (claim 80), and the negative expression of CD34 and CD45 (claim 79) (pg. 20, “Characterization of ADMSCs”- Watanabe; Example 1, pg. 25 of specification- instant case). Additionally, the MSCs of Watanabe et al. were cultured in OriCell Mesenchymal Stem Cell Growth Medium (pg. 18, “Preparation of ADMSCs”), which comprises basal medium and fetal bovine serum (i.e., mammalian serum) (see Cyagen PDF). While the instant claims and working examples of the instant specification fail to teach the culture media composition of the MSCs used, page 15 of the instant specification discloses that in some embodiments, the MSCs may be cultured in media comprising mammalian serum, and Example 1 notes that the MSCs were cultured in “MSC expansion medium”) (pg. 25, para 2).
An Artisan, interested in integrin alpha10-expressing MSCs, would be aware of Varas et al. for teaching the upregulation of integrin alpha10 in MSCs and the resulting characteristics/functions.
Varas et al. teaches increased expression of integrin alpha10 when MSCs are cultured in chondrogenic medium or treated with FGF-2 (Abstract). Varas et al. notes that MSCs express a variety of different integrins that are involved in cellular events, such as proliferation, differentiation, adhesion, and migration, with alpha10 being the main collagen-binding integrin on chondrocytes in cartilage, but is also found on heart valves and tendon (pg. 966, col 1, para 3).
Additionally, Varas et al. teaches the value of integrin-alpha10 as a marker for MSCs in a therapeutic context, stating “Markers defining the differentiation state or differentiation potential of MSCs are important, e.g., when optimizing cultivation systems and to characterize high-quality MSCs used for therapy. Presently, to determine the level of differentiation, the isolated cells have to be tested in time-consuming assays for their differentiation capacity into the osteogenic, adipogenic and chondrogenic lineages. We believe that antibodies recognizing 10- as well as 11-integrins can be of great value in the field of MSC research.” (pg. 976, col 2, para 2).
Since both Watanabe et al. and the instant case teach culturing adipose-derived MSCs in the same manner, one of ordinary skill in the art would conclude that the cells share the same characteristics (as demonstrated by the flow cytometry results) and express the same genes, including integrin alpha10. Further, it would be obvious to an artisan of ordinary skill to obtain a population of at least 60% (or 65%- claim 78) MSCs expressing integrin alpha10 using known techniques/methods in the art, such as FACs (e.g., selected with an anti-integrin alpha10 antibody- claim 87), as evidenced by Varas et al. One would be motivated to select for integrin alpha10 MSCs because as taught by Varas et al., integrin alpha10 is a novel cell surface marker for MSCs with high proliferative activity and sustained chondrogenic potential (chondrocytes form cartilage tissue, which is found in the respiratory system) (pg. 974, col 1-2).
Regarding claim 82, Watanabe et al. teaches the MSCs being administered in a cell suspension with a pharmaceutically acceptable excipient (e.g., saline) (pg. 19, “Lung transplantation and administration of ADMSCs”).
Regarding claim 88, Watanabe et al. teaches the composition further comprising an anti-inflammatory and/or immunomodulatory agent (e.g., tacrolimus) (Abstract).
Response to Arguments
Applicant's arguments filed 12/19/2025 have been fully considered but they are not persuasive.
112(a)/112(b) Rejections:
The Applicant argues that possession is established in the specification for a “therapeutically effective amount” and that the term is definite (regarding 112(b) rejection). This argument is not found to be persuasive, as the Examples cited by the Applicant (e.g., Examples 2 and 3) provide minimal guidance on how one would determine an amount to give to a subject in order to treat ARDS. Example 2 recites administering 5 million integrin alpha10-selected MSC/kg intravenously to pigs. Example 3 does not disclose any dosage or administration route. However, the Applicant fails to provide evidence of how these Examples would lead an artisan understand what a “therapeutically effective amount” is, and fails to address concerns raised in the previous 112(a) written description rejection, such as whether the same dose would result in all the claimed symptoms being treated/prevented.
Additionally, defining a “therapeutically effective amount” by a variable function (increased coagulation time) does not further clarify the metes and bounds of the recitation. For example, increased coagulation time compared to what? By how much? How would an artisan determine this?
The Applicant argues that the claims are enabled, as “it is not necessary to specify the dosage or method of use if it is known to one skilled in the art that such information could be obtained without undue experimentation” (pg. 5 of Remarks). Additionally, the Applicant argues that the art referenced by the Examiner is “simply not the standard for assessing enablement of the present claims”, and that “the articles cited by the Examiner suggest that it would be within the purview of a person of ordinary skill in the art to be familiar with ARDS, including the recognized porcine models of ARDS described in the specification, and to understand the instant disclosure as supporting ARDS treatment by administering a composition comprising integrin a10-selected Mesenchymal Stem Cells (MSCs) to an individual in accordance with the current claims” (pg. 5 of Remarks).
This argument is not persuasive, as the Applicant does not provide evidence or distinctly point out how the teachings of the cited art, such as those stating “the efficacy of MSCs across different modes of administration, dosage, etc. is still unpredictable and has challenges to overcome” would mean there is no “undue experimentation” for an artisan, and why these references suggest that the instant disclosure supports the current claims. Further, the Applicant fails to address the concerns of Han et al. regarding the clinical translation of MSC-based therapies for ARDS, or Wilson et al. regarding the components of the MSC culturing media.
The Applicant also argues that the citation of Ferdowsian et al. “to allege that "an animal model with a deficient protein of interest may not be sufficient as modeling a disease and evaluating therapeutic effects."” (pg. 5) is not the standard for enablement, as it does not correlate with the disclosed or claimed method invention and is not specific to the porcine model of ARDS. Ferdowsian et al. was cited to address the broad genus of subjects treated, which has been addressed with amending the claims to limit the subjects to mammalian subjects.
103 Rejections:
The Applicant argues:
“the disclosure of Zheng would not lead a person of ordinary skill in the art to the claimed methods with any reasonable expectation of success in treating ARDS.”, as “Zheng admits, "the present data are not sufficient to support a conclusion that MSCs exert their effects through alleviating lung inflammation." Zheng, page 6 right column; see also id. at Figure 3, page 6 ("No significant differences were found between the two study groups at any of the time points.").”
Additionally, the Applicant argues:
“there is nothing in Varas that suggests that treating a subject with a population of MSCs that are selected to be alphal0 positive would reduce the inflammation in a subject suffering from acute respiratory distress syndrome (ARDS) and/or associated disorders. Varas discusses the role of integrin alphal0 in relation to collagen type II synthesis, which is a collagen type found predominantly in cartilage, and not as relevant for lung tissue, where predominant collagen types are type I and III. Furthermore, the Examiner argued that "chondrocytes form cartilage tissue, which is found in the respiratory system" as proof that a person of skill in art would be motivated to select for integrin alphal0 as a "surface marker for MSCs with high proliferative activity and sustained chondrogenic potential." Id., page 20. However, ARDS and associated disorders affect alveoli, which do not contain cartilage.”
These arguments are not found to be persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Varas does provide sufficient motivation for an artisan to select for integrin-alpha 10 MSCs. Not only does Varas address the chondrogenic differentiation potential of alpha10-expressing MSCs, but also the high proliferation potential. Varas notes that “MSCs express a variety of different integrins that are involved in cellular events, such as proliferation, differentiation, adhesion, and migration” (pg. 966, col 1, para 3), all of which may be functional advantages in the context of treating ARDS. Additionally, Varas teaches the value of integrin-alpha10 as a marker for MSCs in a therapeutic context, stating “Markers defining the differentiation state or differentiation potential of MSCs are important, e.g., when optimizing cultivation systems and to characterize high-quality MSCs used for therapy. Presently, to determine the level of differentiation, the isolated cells have to be tested in time-consuming assays for their differentiation capacity into the osteogenic, adipogenic and chondrogenic lineages. We believe that antibodies recognizing 10- as well as 11-integrins can be of great value in the field of MSC research.” (pg. 976, col 2, para 2).
In addition, while alveoli may not contain cartilage, the teachings of Varas on the chondrogenic potential of MSCs are still relevant to respiratory disorders such as ARDS, as cartilage is found in the lungs, as evidenced by Gopar-Cuevas, Yareth, et al. ‘Chondrocyte Turnover in Lung Cartilage’. Cartilage Repair and Regeneration, InTech, 14 Feb. 2018. Crossref, https://doi.org/10.5772/intechopen.70860. (Gopar-Cuevas discusses nestin-expressing MSCs, but the teachings of lung chondrocytes in maintaining homeostasis and/or repairing damaged tissue are still relevant- see pg. 34, “5. Cell renewal in lung cartilage”, for example).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant's argument that the homogenous composition comprising integrin a10-selected MSCs of amended claim 74 has a higher efficacy in treatment of ARDS and related disorders, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The Examiner notes that in the heading of the 103 rejection as the claims being unpatentable over Watanabe et al. and Varas et al., the Examiner accidentally noted only claims 86 and 88 as rejected. However, in the rejection, the teachings of Watanabe et al. and Varas et al. address the limitations of claims 74, 77-82, 84-88, and 90 (with dependents specifically being noted).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638
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