Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restrictions
Applicant's election without traverse of Group II in the reply filed on 04/17/2026 is acknowledged.
Status of the Application
Claims 1-31 are pending. Claim 9 is rejoined with the elected group. Claims 1-12, 18 and 19 are currently under examination. Claims 13-17 and 20-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Example 1 lists several hyperlinks and/or other forms of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms ATCC and LIPOFECTAMINE, which are trade names or marks used in commerce, has been noted in this application in Example 1. Each term should be accompanied by the generic terminology; furthermore each term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 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.
Claim(s) 1, 3, 5, 7 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Holst et al (Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion, Cell Reports, 2017, 20(8), pp. 1893-1905 of record P.237.IN 09/15/2023).
Regarding claims 1 and 19, Holst et al. teach that a decrease in surface tension in plasma membranes (PM) is buffered by the internalization of the PM lipid bilayer by GRAF1, and that disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol-interacting amino acids in the protein promotes the 3D motility of cancer cells (abstract) and teach methods of inhibiting cancer cell invasion comprising administering GRAF1 to SW480 cancer cells (see page 1901 and Figure 5A and B). GRAF1 was administered in solution amenable to cell culture (page 1903 cell culture and assay) and thus meets the limitations of a composition of claim 19.
Regarding claims 3 and 5, the method step of increasing the tension of the plasma membrane would inherently increase the pressure of the cell and increase or decrease a component of the plasma membrane.
Regarding claim 7, Holst et al. teach the cells expression GRAF1 and thus meet the limitation of the claim.
Thus Holst et al. anticipates the instant claims.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-12, 18 and 19 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 methods of knocking down expression of genes ERM, RHOA, SLK, STK10, MTSSIL, FBP17 and CIP4 in cells in vitro using a siRNA and in vitro invasion and migration of MDA-MB-231 cells wherein no amoeboid-like movement was observed in ERM-knockdown cells and further administering GRAF1 to a SW480 cancer cell inhibiting cancer cell invasion in vitro (see 102 rejection),
does not reasonably provide enablement for methods of treating any cancer by contacting the cancer cell with any agent to increase tension of a plasma member in the cancer cells and wherein the agent causes an increase in membrane-actin cortex attachment, wherein the agent is an expression vector comprising a PIP5K, wherein the agent increases phosphorylation of ERM proteins, wherein the phosphorylation increases a kinase protein and wherein the agent is an expression vector to express an ezrin fusion protein.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The following factors have been considered in the analysis of enablement: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims and the nature of the invention:
The broadest reasonable interpretation of the claims is a method of treating any type of cancer using any type of agent that when administered to the cancer cell, increases tension of a plasma membrane of the cancer cell and treats cancer.
Whether the specification would have been enabling as of the filing date involves consideration of the nature of the invention, the state of the prior art, and the level of skill in the art. The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification.
The state of the prior art:
A thorough review of the patent and non-patent literature indicates that the state of the art demonstrating treating any cancer cell by contacting the cancer with an agent to increase tension of a plasma membrane was nascent at the time of filing. Song et al. (of record cited on P.237.IN filed 09/15/2023) teach Ezrin, encoded by the EZR gene, facilitates numerous signal transductions in tumorigenesis and mediates diverse essential functions through interactions with a variety of growth factor receptors and adhesion molecules. Song et al. teach emerging evidence has demonstrated that Ezrin is an oncogene protein, as high levels of Ezrin are associated with metastatic behavior in various types of cancer (abstract). Song further teach Ezrin controls signaling transduction by interacting with adhesion molecules and various growth factor receptors and increased Ezrin expression is correlated with poor prognoses in various cancers (abstract).
Dias et al. ("Plasma membrane integrity in health and disease: significance and therapeutic potential." Cell discovery 7.1 (2021)) teach maintenance of plasma membrane integrity is essential for normal cell viability and function. Thus, robust membrane repair mechanisms have evolved to counteract the eminent threat of a torn plasma membrane which is an immediate threat to cell survival (see abstract and page 2 first para.). Dias et al. teach loss of plasma membrane tension can cause a host of different conditions such as an increase in invasive cancer cells (see Fig 1 and explanation page 4). Dias et al. does not teach administration of any agent to any type of cancer cell would increase tension of the plasma membrane and treat any cancer.
Holst et al. (cited above) teach that a decrease in surface tension in plasma membranes (PM) is buffered by the internalization of the PM lipid bilayer by GRAF1, and that disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol-interacting amino acids in the protein promotes the 3D motility of cancer cells (abstract) and teach methods of inhibiting cancer cell invasion comprising administering GRAF1 to SW480 cancer cells (see page 1901 and Figure 5A and B).
While the prior art teach a correlation between using GRAF1 and tension of plasma membrane in a SW480 cancer cell, a review of the prior art does not provide a correlation between any agent such as, Ezrin expression or lack thereof in cancer cells and effects on tension of a plasma membrane in a cancer cell such that administration of any agent would treat the cancer cell.
Moreover, Applicant’s own studies does not provide a predictable correlation between administration of any agent to any cancer cell and an increase in the tension of a plasma membrane that led to a treatment of any cancer. Tsujita et al. teach using siRNA to target BAR proteins suggest that low-tension-mediated mechanosignaling by BAR proteins plays a pivotal role in cancer cell motility, whose mechanisms are normally suppressed by homeostatic PM tension in non-motile epithelial cells (page 6 last para.). Tsujita et al. ("Homeostatic membrane tension constrains cancer cell dissemination by counteracting BAR protein assembly." Nature communications 12.1 (2021): 5930 of record IDS 09/15/2023) also teach cancer cells are known to exploit collective migration characterized by multicellular coordination through cell–cell adhesion for dissemination16. Such collective processes are mechanically mediated by the coordination between the cell adhesion forces and actomyosin contractility71. It will be interesting to investigate how PM tension integrates with these forces to control collective migration and whether manipulating PM tension could suppress this type of movement. (see page 8 second para). Thus Tsujita et al. questions whether manipulating plasma membrane in cancer cells would work to inhibit the migration of cancer cells. Tsujita et al. concludes [a]bnormal changes in the cell membrane shape, including the formation of microvesicles/exosomes and micropinocytosis, are hallmarks of cancer. It is tempting to speculate that these function could be directly controlled by PM tension. Our findings provide a foundation for future investigations into whether MCA manipulation can be exploited for therapeutic interventions aimed at normalizing cell membrane mechanics.
The level of one of ordinary skill:
While the level of one of ordinary skill practicing said invention would be high, the level of predictability is considered variable as evident in the prior art discussed above and is not considered to provide sufficient enablement to practice the claimed invention.
Because the state of the prior art does not provide evidence of the degree of predictability that administration of any agent to a cancer cell would increase the tension of a plasma membrane and treat the cancer cell, one of ordinary skill in the art would look for guidance or direction in the instant specification.
The level of predictability in the art:
“The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability.” (MPEP 2164.03).
The amount of direction provided by the inventor:
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, 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). In this case, little is known about what agents, when administered to a cancer cell, would increase the tension in the plasma membrane of a cancer cell.
The existence of working examples:
The working embodiment in the instant application describes methods of knocking down expression of genes ERM, RHOA, SLK, STK10, MTSSIL, FBP17 and CIP4 in cells in vitro and in vitro invasion and migration of MDA-MB-231 cells wherein no amoeboid-like movement was observed in ERM-knockdown cells. The working embodiments do not describe using any agent when administered to a cancer cell would increase the tension of the plasma membrane and treat the cancer.
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant invention suggests using any agent targeted to any gene or protein, at its breadth, for treatment of any type of cancer.
While the MPEP 2164.02 states the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970), the lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The prior art is undeveloped for the role any agent plays in increasing the tension of a plasma membrane in a cell and the specification does not provide sufficient guidance. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
Written Description
Claims 1-12, 18 and 19 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art.
Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “…disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.” Thus when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The claims are drawn to a genus of agents with the function of increasing the tension of a plasma membrane when administered to a cancer cell and treatment of any cancer cell.
When determining 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. In the instant case, the specification describes a knocking down expression of genes ERM, RHOA, SLK, STK10, MTSSIL, FBP17 and CIP4 in cells in vitro using a siRNA (Example 5). The specification does not describe a genus of agents that would increase the tension of a plasma membrane in any type of cancer cell. The embodiment does not encompass the vast number of different types of agents which could be nucleic acid inhibitors, gene editing systems, antibodies, small molecules or chemical compounds, for example.
It is then determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genera. In the instant case, the only other identifying characteristics are inhibition of expression of genes ERM, RHOA, SLK, STK10, MTSSIL, FBP17 and CIP4 in cells. Such functional limitations cannot be identifying characteristics for the vast number of agents claimed. The disclosure has not described any other agent with the functional characteristics of increasing tension in plasma membranes, particularly given there is no association between these genes and effects on plasma membrane tension in cancer cells. A review of the specification shows that it provides no description or guidance that would allow one of skill to distinguish the functional species of the recited structural genus from the non-functional members without empirical determination.
Since the disclosure and the prior art fail to describe the common attributes and characteristics concisely identifying members of the proposed genus, and because the claimed genus is highly variant a vast number of agents with the function of increasing the tension of a plasma membrane in any type of cancer, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus claimed.
"A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
Further, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
Thus the specification and claims lack written description because it is clear that Applicant did not have possession of every type of agent. There is substantial variation in the genus of agents. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521,222 USPQ 369,372-372 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Chong at (571)272-3111. The examiner can normally be reached Monday thru Friday between M-F 8:00am-4:30pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/
Primary Examiner Art Unit 1636
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