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 .
Status of Claims
Claims 1-20 are pending.
Priority
Claims 1-20 has priority to PRO 63/293,742 filed on December 24, 2021.
Drawings
The drawings are objected to because:
The drawings are presented in color, but no petition for color drawings has been filed or accepted by the USPTO.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 10, 11, 12, 13, 14, 15, and 16 are objected to because of the following informalities:
Claim 10 recites “hematopoietic stem cell is non-adherent” should read “hematopoietic stem cells are non-adherent”.
Claim 11 recites “hematopoietic stem cell is non-adherent” should read “hematopoietic stem cells are adherent”.
Claim 12 recites “hematopoietic stem cell is exposed” should read “hematopoietic stem cells are exposed”.
Claim 13 recites “hematopoietic stem cell expresses” should read “hematopoietic stem cells express
Claim 14 recites “hematopoietic stem cell expresses” should read “hematopoietic stem cells express
Claim 15 recites “hematopoietic stem cell expresses” should read “hematopoietic stem cells express
Claim 16 recites “hematopoietic stem cell expresses” should read “hematopoietic stem cells express
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Applicant is advised that should claim 1 be found allowable, claim 4 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). Claim 4 recites a method of Claim 1 where the cancer is treated by administering neuronal or neuronal-like cells. However, Claim 1 is directed to administering a neuronal population for the purpose of treating cancer. Claim 4 is merely restating the neuronal population of claim 1 using different terminology. Thus, despite the difference in wording, these claims have substantially the same scope.
Applicant is advised that should claim 1 be found allowable, claim 6 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). Claim 6 recites administering neuronal or neuronal-like cells that are in an immature state. However, the language of Claim 1 already encompasses immature neuronal or neuronal-like cells in an immature state given that Claim 1 is directed to a neuronal population. Thus, despite the difference in language, these claims have substantially the same scope.
Applicant is advised that should claim 1 be found allowable, claim 7 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). Claim 7 recites the immature neuronal or neuronal-like cells are allowed to differentiate. However, both Claims 6 and 7 are merely identifying specific development states that are already encompassed by the generic language of neuronal population of Claim 1. Thus, despite the difference in language, these claims have substantially the same scope.
Applicant is advised that should claim 18 be found allowable, claim 20 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). Claim 18 recites that the naturally occurring mesenchymal stem cells are derived from tissue. Claim 18 already states the mesenchymal stem cells are naturally occurring. Naturally occurring mesenchymal stem cells are necessarily obtained from tissue given that tissue is the natural source of mesenchymal stem cells. Thus, despite the difference in language, these claims have substantially the same scope.
Claim Rejections - 35 USC § 112
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 1-20 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The nature of the invention:
The claimed invention is directed to a method for treating cancer and overcoming cancer-associated immune suppression by administering a neuronal population, specifically, neuronal and neuronal-like cells. The scope encompasses both mesenchymal stem cells and hematopoietic stem cells exhibiting neuronal-like characteristics and/or neuronal-like markers.
Breadth of the claims:
The claims encompass various stem cell types, as well as neuronal cells, without specifying particular markers, culture conditions, or methods for inducing neuronal-like features. For example, Claim 9 is directed to hematopoietic stem cells that both maintain hematopoietic stem cell properties and neuronal-like characteristics. Given this and the generic scope of neuronal or neuronal-like cells, the claims are overly broad and include an untold number of possible markers and/or structural features that are characteristic of neuronal cells in general.
The amount of direction or guidance present in the Application:
The specification offers minimal guidance with the sole working example involving culturing mesenchymal stem cells purchased from a biotech supplier and culturing the mesenchymal stem cells in a neural stem cell medium composed of DMEM/F12, B-27 supplement without vitamin A, epidermal growth factor, fibroblast growth factor, and mouse leukemia inhibitory factor [¶ 00314]. From there, the mesenchymal stem cells were replated and incubated with alpha-modified minimum essential medium that contained mM Beta-mercapthoethanol [¶ 00315]. These mesenchymal stem cells were further subjected to additional culturing consisting of media designed to induce neurogenic cell differentiation [Id.]. However, the specification makes no mention that any of this was successful by confirming the presence or absence of neural-like cell factors such as cellular functions or markers. In simple terms, the specification recites a method for culturing and maintaining stem cells with no verification of any neural or neural-like cell characteristic being present.
With respect to hematopoietic stem cells, the specification provides no guidance for culturing or maintaining hematopoietic stem cells or embodiments for administrating hematopoietic stem cells in the tumor context.
Additionally, the specification provides no guidance as to what type or amount of immune cell infiltrate should be present in order for a patient to be eligible for said “treatments”. The only relevant examples provided, aside from the mesenchymal stem cell culture media conditions, are where Applicant replicated a tumor microenvironment where these tumor microenvironments simulated specific aspects on cancer immune suppression, e.g. IL-10 induced immune suppression. These tumor microenvironments were then subjected to nerve growth factor and analyzed for the presence, or lack thereof, of suppressed natural killer cell activity [¶ 00306, 00307, 00308, 00309, 00310, 00311, 00312, 00313, 00314].
Presence or absence of working examples:
The only working example that involves the use of administering cells of any type is provided in the example above where mesenchymal stem cells were cultured in a neural stem cell medium and then administered to mouse models that were injected with several types of cancer, e.g. B16 melanoma, 4T1 breast cancer, etc. [¶ 00316]. Aside from that, the only other examples provided are the tumor microenvironments that were directed to a specific type of cancer immune suppression, e.g. IL-10, and the tumor microenvironment was exposed to neural growth factor and analyzed for natural killer cell activity.
Relative skill of those in the Art:
The relative skill in the art, is that of a scientist with several years’ experience in the field, but the Art itself is a recognition of what is understood by the Artisan, and thus, as seen below, does not make the breadth of the claims more predictable.
The predictability or lack thereof in the art:
The behavior of stem cells in the tumor microenvironment is highly unpredictable. As Gonzalez et al. notes, tumors often evolve mechanisms that mimic peripheral tolerance to avoid immune attack, potentially leading to immune suppression and metastatic progression [Abstract, Roles of the immune system in cancer: from tumor initiation to metastatic progression, Genes Dev., 2018]. As Gonzalez notes, advanced cancers exhibit recruitment of inflammatory cells, immune evasion, angiogenesis, extracellular matrix remodeling, fibrosis, proliferation, anti-apoptotic pathways, and metastatic dissemination [Fig. 1]. Additionally, an article written by Minev et al. discussed the current hazards associated with stem cells and their use in treating cancer [Mesenchymal stem cells in cancer immunotherapy: promises and challenges, Oncotarget, 2024]. The article stated that despite some promising results in some clinical trials, other clinical trials have shown the complexities of mesenchymal stem cell behavior, including variability in their effects and the potential to create conditions that support tumor growth [¶ 3]. Lastly, the specification provides no guidance on how an Artisan would address the preventing of cells, after administration, from being functionally suppressed or co-opted by the tumor microenvironment.
Quantity of experimentation needed:
Given the lack of guidance on generating neuronal-like hematopoietic stem cells, or the showing of neuronal-like characteristics of mesenchymal stem cells after culturing in neuronal stem cell promoting media; how either of these two stem cell types would maintain their dual functionality; or how an Artisan could administer these cells to ensure these cells overcome tumor-induced immune suppression, an Artisan would be required to conduct extensive, undirected experimentation in order to determine appropriate cell types, culture conditions, differentiation protocols, and administration methods.
Such is considered un experimentation, as it is required for all combinations of experimentation, appropriate cell types directed at different cancer types, and administration methods.
Conclusion:
Thus, the claims are not considered enabled.
Claim Rejections - 35 USC § 112
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 1-20 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.
Claim 1 uses the generic term “neuronal population” or “neuronal or neuronal-like cells” in reference to a treatment that is being administered to a patient that is suffering from a tumor and is used to overcome associated immune suppression observed in cancer. The same generic scope of “neuronal population” is present in each of the dependent claims, i.e. 2-20.
Claim 4 uses the generic term “neuronal population” or “neuronal or neuronal-like cells” in reference to a treatment that is being administered to a patient that is suffering from a tumor and is used to overcome associated immune suppression observed in cancer.
Claim 5 uses the generic term “neuronal population” or “neuronal or neuronal-like cells” in reference to a treatment that is being administered to a patient that is suffering from a tumor and is used to overcome associated immune suppression observed in cancer.
Claim 6 uses the generic term “neuronal population” or “neuronal or neuronal-like cells” in reference to a treatment that is being administered to a patient that is suffering from a tumor and is used to overcome associated immune suppression observed in cancer.
Claim 7 uses the generic term “neuronal population” or “neuronal or neuronal-like cells” in reference to a treatment that is being administered to a patient that is suffering from a tumor and is used to overcome associated immune suppression observed in cancer.
The specification provides antecedent basis for neuronal population as it relates to the neuronal population being administered to a patient suffering from tumor for the purpose of treating or overcoming the associated immune suppression associated with cancer [¶ 0014].
Applicant’s specification states the neuronal population are neuronal and neuronal type cells [¶ 00125]. It goes on to state the neuronal or neuronal-like cells are derived from hematopoietic stem cells or mesenchymal stem cells [¶ 0099, 00127]. It further gives a description of where the mesenchymal stem cells can be derived from, e.g. bone marrow, perivascular tissue, adipose tissue, etc [¶ 00130]. At paragraph [00183], Applicant states that some embodiments include the use of embryonic stem cells differentiated into neuronal lineage cells. In another example, Applicant states that in some embodiments dopaminergic neurons are needed and that generation of said cells from embryonic stem cells is known in the art [¶ 00185]. The specification further states that terminal cells are characterized for neuronal and serotonergic markers [¶ 00190]. Starting a paragraph [00191], the specification goes on to list numerous neuronal markers. Paragraphs [00299] through [00305] discusses the use of mesenchymal stem cells in the treatment of Amyotrophic lateral sclerosis (ALS). Example 9 provides the only example where mesenchymal stem cells were cultured in order to exhibit neuronal-like features [¶ 00314]. Lastly, the specification states that in Figures 9A through 9E, mice were injected with different types of cancers. However, the specification does not describe or provide examples of the broader range of neuronal type cell types, differentiation types, or functional subpopulations that make up “neuronal population. “Neuronal population” encompasses multiple subtypes such as excitatory neurons, inhibitory neurons, glutamatergic neurons, GABAergic neurons, and other types neuronal phenotypes [Cell Signaling Technology, Neuronal and Glial Cell Markers, January 2021]. Moreover, each neuronal subtype is characterized by a distinct set of markers, one of ordinary skill in the art would not understand from the disclosure that the one example given for mesenchymal stem cells would encompass the entire genus of neuronal cell types and markers associated with these types of cells.
Given the generic term “neuronal population” or “neuronal or neuronal-like cells” as it relates to treating a patient with tumor exhibiting cancer associated immune suppression, and the absence of teaching of what other neuronal cells or neuronal-like cells could be used for said treatment, an Artisan would not understand Applicant to be in possession of the full generic scope of “neuronal population” for administering to a patient suffering from a tumor exhibiting cancer associated immune suppression.
Claims 8-16 as well as Claims 1-7 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.
Claim 13 uses the generic term “interleukin-3 receptor” as it relates to a hematopoietic stem cell expressing the receptor for purposes of the hematopoietic stem cell being used as a neuronal-like cell in the treatment of cancer.
Claim 14 uses the generic term “interleukin-1 receptor” as it relates to a hematopoietic stem cell expressing the receptor for purposes of the hematopoietic stem cell being used as a neuronal-like cell in the treatment of cancer.
Claim 15 uses the generic term “c-Met” as it relates to a hematopoietic stem cell expressing the cell surface receptor as it relates to a hematopoietic stem cell being used as a neuronal-like cell in the treatment of cancer.
Claim 16 uses the generic term “Mpl” as it relates to a hematopoietic stem cell expressing the cell surface marker as it relates to a hematopoietic stem cell being used as neuronal-like cell in the treatment of cancer.
The specification provides antecedent basis for “interleukin-3 receptor”, “interleukin-1 receptor”, “c-Met”, and “Mpl” at paragraphs [0028], [00183], [00107], and [00107] respectively.
Applicant’s specification only mention of interleukin-3 (IL-3) receptor in the specification occurs in the generic recitation in paragraphs [00104, 0072, 0028]. No experimental examples or data are provided showing IL-3 expression in hematopoietic stem cells.
With respect to interleukin-1 (IL-1) receptor, the specification mentions IL-1 in unrelated contexts. It is referenced in connection with an IL-1/glial cell line derived neurotrophic factor [¶ 000183]. IL-1 is described as being present in umbilical cord-derived endothelial adherent cells at [00027]. And, it is listed as a number of anti-inflammatory agents recommended as adjuvants [¶ 000297]. Lastly, IL-1 and NGF are added exogenously to human monocytes at paragraph [000307]. None of these passages provide any disclosure of IL-1 expression being present in hematopoietic stem cells.
With respect to c-Met, the only disclosure referencing c-Met in the specification occurs in an example relating to endothelial progenitor cells in placental endothelium vaccines, e.g. ValloVax [¶ 000107]. There is no further mention of c-Met, much less being expressed in hematopoietic stem cells.
With respect to Mpl, the only mention of Mpl occurs in paragraph [000107], where it is recited without further characterization. There are no examples or experimental data are provided demonstrating Mpl expression in hematopoietic stem cells for the claimed invention.
However, Rix et al. discuss numerous markers associated with hematopoietic stem cells that are relevant in identifying beyond what is “disclosed” in the claims and specification [Markers for hematopoietic stem cells: the disconnect between an identification marker and its function, Front Physiol, 2022]. For example, Figure 1 illustrates expression of CD34, c-Kit, CD49f, CD90, RET, and EPCR, while Table 1 lists CD45 as a regulator of motility and hematopoietic progenitor function. Rix et al. goes on to discuss numerous markers that are indicative of hematopoietic stem cells that include a number of well-studied markers. Based on this, and the lack of confirmation provided in the specification, a person of ordinary skill would not know what to look for in determining the presence or absence of hematopoietic stem cells for use in culturing these cells to express neuronal-like cell markers for administration in a cancer treatment.
Given the generic scope of “interleukin-3 receptor”, “interleukin-1 receptor”, “c-Met”, and “Mpl” as it relates to receptors being expressed in hematopoietic stem cells for the purpose of culturing these cells to express neuronal-like markers, and the absence of teaching of what other markers could be present that would also be indicative of viable hematopoietic stem cells capable of being used in a culture condition for generating hematopoietic stem cells that display neuronal-like markers while also retaining markers indicative of hematopoietic stem cells, an Artisan would not understand Applicant to in possession of the generic scope of “interleukin-3”, “interleukin-1”, “c-Met”, and “Mpl” as it relates to identifiable markers for culturing hematopoietic stem cells to generate neuronal-like characteristics.
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, 2, 3, 9, 12, 13, 18, 19, and 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 recites “overcoming cancer associated immune suppression”. The term “overcoming” is unclear. Does this require complete reversal of cancer associated immune suppression? Does it only require a partial reversal of the immune suppression characteristics associated with cancer? Or, is it merely a detectable change in the immune suppression affects of cancer, e.g. a change in viscoelastic properties?
Claim 1 recites “selecting a patient suffering from a tumor”. As written, this term is unclear. What constitutes “suffering”? Does suffering encompass benign or malignant tumors? Does the patient have to be symptomatic, or can the patient be asymptomatic? Or does the phrase simply mean there has been a clinical diagnosis that a tumor is present?
Claim 2 recites “based on the amount of immune cell infiltration”. It is unclear what level of immune cell infiltration is sufficient. Secondly, immune cell infiltration is not defined. Is the determination based on one particular immune cell, or is it based on the presence of all types of immune cells known to infiltrate a tumor or is the determination based on an increase or decrease in the presence of immune cells within the tumor. Additionally, there is no quantitative threshold provided in order for a person of ordinary skill to determine what amount is required for selecting a patient.
Claim 3 recites the limitation "cellular infiltration" in Line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 9 recites “hematopoietic stem cells are capable of generating leukocytic…cells”. The phrase “capable of generating” is unclear and does not provide an objective means for determining whether a hematopoietic stem cell is capable of satisfying the claim limitation.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 9 recites the broad recitation “leukocytic…cells”, and the claim also recites “lymphocytic…cells” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 12 recites “hematopoietic stem cell is exposed to hypothermia”. As written, “hypothermia” is unclear because there is no temperature range provided. Hypothermia is generally understood to be a temperature below normal physiological temperature, e.g. around 37˚C for mammals. Given this, mild hypothermia typically sets in around 32˚C to 35˚C, or is a more severe form of “hypothermia” required. An Artisan would not understand the metes and bounds as it relates to “hypothermia” given the broad temperature range making up “hypothermia”.
Claim 13 recites the limitation "interleukin-1" in Line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 18 recites the limitation "mesenchymal stem cells" in Line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "mesenchymal stem cells" in Line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites “mesenchymal stem cells are generated in vitro”. The term “generated” is unclear in this instance. Are the mesenchymal stem cells “generated” using from culturing adherent stromal cells, differentiating pluripotent stem cells, or expanding tissue derived mesenchymal stem cells through passaging.
Claim 20 recites the limitation "mesenchymal stem cells" in Line 1. There is insufficient antecedent basis for this limitation in the claim.
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, 4, 5, 6, and 7 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by Bago et al. [Neural stem cell therapy for cancer, Methods, 2017].
Regarding claim 1, Bago et al. teaches a method of treating cancer and/or overcoming cancer [Abstract] associated with immune suppression comprising the steps of: a) selecting a patient suffering from a tumor [Abstract]; and b) administering to said patient a neuronal population grown ex vivo [3.1 Endogenous NSCs ¶ 1].
Regarding claim 4, Bago et al. teaches the method of claim 1, wherein said cancer is treated by administration of neuronal or neuronal-like cells [5.1 Enzyme/prodrug ¶ 3].
Regarding claim 5, Bago et al. teaches the method of claim 4, wherein said neuronal or neuronal-like cells are administered intratumorally [5.1 Enzyme/prodrug ¶ 3].
Regarding claim 6, Bago et al. teaches the method of claim 5, wherein said neuronal or neuronal-like cells are administered in an immature state [Abstract].
Regarding claim 7, Bago et al. teaches the method of claim 6, wherein said immature neuronal or neuronal-like cells are allowed to differentiate intratumorally [Introduction ¶ 1].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 2, 3, and 8-20 are rejected under 35 U.S.C. §103 as being unpatentable over Bago et al. [Neural stem cell therapy for cancer, Methods, 2017], in view of Stoll et al. [Immune infiltrate in cancer, Aging (Albany NY), 2015], in view of Mondragon-Garcia et al. (Hereinafter Garcia) [Human cord blood hematopoietic cells acquire neural features when cultured in the presence of cytokines, Blood cells, Molecules, and Diseases, November 2020], in view of Erol et al. [Effects of storage media, supplements and cryopreservation methods on quality of stem cells, World J Stem Cells, Sept. 2021], in view of Jahandideh et al. [The pro-inflammatory cytokines effects on mobilization, self-renewal and differentiation of hematopoietic stem cells, Human Immunology, 2020], in view of Tesio et al. [Enhanced c-Met activity promotes G-CSF-induces mobilization of hematopoietic progenitor cells via ROS signaling, Hematopoiesis and Stem Cells, 2011], in view of Yoshihara et al. [Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblast niche, Cell Stem Cell, 2007], in view of Hernandez et al. [Differentiation of human mesenchymal stem cells towards neuronal lineage: clinical trials in nervous system disorders, Biomol Ther (Seoul), 2019], in view of Dupuis and Oltra (Hereinafter Oltra) [Methods to produce induced pluripotent stem cell-derived mesenchymal stem cells: mesenchymal stem cells from induced pluripotent stem cells, World J Stem Cells, Aug. 2021].
Bago et al. teaches all the elements in claims 1, 4, 5, 6, and 7.
Bago et al. does not disclose the limitations found in claim 2.
For claim 2 where the patient is selected based on the amount of immune cell infiltration, Stoll et al., discussing the organization aspect of local inflammatory and immune responses are influenced by the organ in which the tumor develops, discloses that the minimal immune system within a tumor requires only two cell types, i.e. dendritic cells and cytotoxic T lymphocytes where the dendritic cells would engulf portions of the cancer cell in order to cross-present tumor associated antigens to the cytotoxic T lymphocytes. The cytotoxic T lymphocytes would then attach the malignant cells [Introduction ¶ 2].
For claim 3 where the cellular infiltrate is comprised of tumor infiltrating lymphocytes, Stoll et al. disclosed that cytotoxic T lymphocytes were present as infiltrate along with dendritic cells [Introduction ¶ 1-2].
It would have been prima facie obvious to a person of ordinary skill in the art before the filing of the claimed invention to modify the methods and systems of Bago et al. that disclosed a method for using immature neuronal type cells in the treatment of cancerous tumors with the teachings of Stroll et al. where the researchers discussed the presence of immune cell infiltrate in the form of dendritic cells and cytotoxic T lymphocytes. Therefore, there is a reasonable expectation of success that a person of ordinary skill in the art would use the immune cell infiltrate as a means for diagnosing a tumor in order to determine if that tumor was an ideal candidate for treating the tumor with a population of neuronal cells grown ex vivo.
For claim 8 where the immature neuronal or neuronal-like cells are derived from hematopoietic stem cells, Garcia, discussing growing hematopoietic stem cells in vitro under culture conditions that displayed neural cell like conditions, discloses exposing hematopoietic cells, including hematopoietic stem cells, to culture conditions that induced neural cell like markers [Abstract]. However, it was also noted that these hematopoietic stem cells also retained expression of hematopoietic markers and did not exhibit any true trans differentiation [Abstract].
For claim 9 where the hematopoietic stem cells are capable of generating leukocytic cells and other cells associated with hematopoietic stem cells, Garcia disclosed that despite the hematopoietic stem cells exhibiting neural cell markers, the hematopoietic stem cells maintained markers associated with these markers still maintained their ability to differentiate into immune type cells [Highlights Point 3].
For claim 10 where the hematopoietic stem cells are non-adherent, Garcia discloses that researchers analyzed the morphology of the non-adherent cells generated in culture [2.5 Morphologic analysis].
For Claim 11 where the hematopoietic stem cells are adherent, Garcia discloses that researchers also analyzed the morphology of adherent cells [2.5 Morphologic analysis].
Here, it would have been prima facie obvious to a person of ordinary skill in the art to modify the systems and methods of Bago et al. that disclosed a method for using immature neuronal type cells in the treatment of cancerous tumors with the teachings of Garcia et al. which demonstrated that hematopoietic stem cells could be induced to express neural cell markers while still retaining hematopoietic stem cell markers and without going through trans differentiation with the additional teachings of Garcia establishing hematopoietic stem cells, and hematopoietic cells, can be cultured under both adherent and non-adherent conditions. Because of this, there is a reasonable expectation of success that the teachings of Bago et al. combined with the additional teachings of Garcia would lead a person of ordinary skill to expect hematopoietic stem cells, capable of exhibiting neural cell markers and maintained under proper culture conditions, could functionally substitute for neural stem cells in cancer treatment strategies, and therefore achieving the therapeutic goals as described in Bago et al.
For claim 12 where the hematopoietic stem cells are exposed to hypothermia, Erol et al., discussing effects of storage media and cryopreservation methods, discloses stem cells, in general, are often frozen using standard protocols that have been optimized for use with cell lines and that DMSO remains to the cryoprotectant of choice even with stem cells [Conclusion]. However, there are a broad range of alternatives to DMSO that hold promise for use as cryoprotectant for stem cells [Id.]. Here there is a reasonable expectation of success that a person of ordinary skill would understand the teachings of Erol et al. combined with the teachings of Bago et al. to understand that hematopoietic stem cells, as well as other stem cell types, are capable of being frozen in the presence of a cryoprotectant. Because of this, it is prima facie obvious to a person of ordinary skill to combine the teachings of Bago et al. with the additional teachings of Erol et al. in order to preserve stem cells, including hematopoietic stem cells, in a cold environment that includes freezing the stem cells in the presence of a cryoprotectant under proper protocols.
For claim 13 where hematopoietic stem cells express interleukin-3, Jahandideh et al. discloses that hematopoietic stem cell possesses a receptor an interleukin-3 receptor [Abstract].
For claim 14 where hematopoietic stem cells express interleukin-1 receptor, Jahandideh et al. discloses the presence of an interleukin-1 receptor since pro-inflammatory cytokines like inerleukin-1 provoke different responses in hematopoietic stem cells [Abstract]. Here, it is prima facie obvious to a person of ordinary skill prior to the filing of the claimed invention and based on the teachings of Jahandideh et al., that an Artisan would recognize the need to identify certain cell markers, including the presence of certain cytokine receptors, in order to determine the presence of hematopoietic stem cells.
For claim 15 where the hematopoietic stem cells express c-Met, Tesio et al. discloses c-Met, the receptor tyrosine kinase encoded by the MET proto-oncogene and has a high affinity to hepatocyte growth factor, is expressed in subsets of hematopoietic stem and progenitor cells [Abstract].
For claim 16 where the hematopoietic stem cell expresses Mpl, Yoshihara et al. discloses that Mpl, also known as CD110, is a cell surface marker receptor for thrombopoietin, which is involved in primary cytokine regulating platelet production and hematopoietic stem cells and is expressed in subsets of primitive CD34 hematopoietic stem cells [Introduction ¶ 3]. Here it would have been prima facie obvious to a person of ordinary skill in the art, based on the teachings of both Tesio et al. and Yoshihara et al, would identify certain markers that could be used as confirmation of the presence of viable hematopoietic stem cells for their use in being cultured to express neural cell like markers and then administered in a cancer treatment as a replacement for neural stem cells as described in Bago et al.
For claim 17 where the neuronal or neuronal-like cells are immature cells generated from mesenchymal stem cells, Hernandez et al. discloses the use of mesenchymal stem cells that have been differentiated towards neuronal cell lineage in the treatment of various diseases [Abstract].
For claim 18 where the mesenchymal stem cells are naturally occurring, Hernandez et al. discloses the use of autologous mesenchymal stem cells being administered via intravenous transplantation [Table 2].
For claim 19 where the mesenchymal stem cells are generated in vitro, Hernandez et al. disclosed the use of culture media to induce differentiation of mesenchymal stem cells [Fig. 1].
For claim 20 where the mesenchymal stem cells are tissue derived, Hernandez et al. discloses the use of autologous stem cells in numerous treatments that are involved in ongoing clinical trials [Table 2], and because the mesenchymal stem cells were derived directly from the patients and mesenchymal stem cells reside naturally in tissue, the autologous stem cells used in the clinical trials discussed in Table 2 are derived from tissue.
it is prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Bago et al. where neuronal stem cells were used in the treatment of tumors with the additional teachings of Hernandez et al. where mesenchymal stem cells were differentiated to display neuronal cell type markers. Because of this, there is a reasonable expectation of success that an Artisan combining the teachings of Bago et al. with the teachings of Hernandez et al. would conclude that it was possible to culture mesenchymal stem cells to display neuronal cell type markers and that these altered stem cells could be used in place of the neuronal stem cells as described in Bago et al.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638