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
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.
Response to Amendments
Applicant’s amendments and response filed May 6, 2026 have been received and entered into the case.
Status of the Claims
Claims 9, 10 and 23 are currently pending.
Claims 9, 10 and 23 are amended.
Claims 1-8 and 11-22 are cancelled.
Claims 9, 10 and 23 have been considered on the merits.
Claim Rejections - 35 USC § 112
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) for written description and enablement are revised due to 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 9, 10 and 23 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 claims 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 inventors, at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a method of inhibiting osteoclast differentiation activity and a method for promoting expression of osteoarthritis inducing factors by administering a composition comprising an inhibitor of a COTL1 protein or an inhibitor of a gene encoding the same selected from the group consisting of antisense nucleotides complementarily binding to COTL1 mRNA, small interfering RNA (siRNA), short hairpin RNA (shRNA), antibodies, peptides, aptamers, compounds, and natural products specifically binding to COTL1 as an active ingredient to a subject. All of these listed categories of inhibitors have a wide array of activities and/or effects. Thus, the claims are broadly drawn to any compound or molecule which acts as an inhibitor of the protein or the gene of COTL1 that is one of the following: an antisense nucleotide complementarily binding to COTL1 mRNA, a siRNA, a shRNA, an antibody, a peptide, an aptamers, a compound, and or a natural product specifically binding to COTL1,
Therefore, the claims are considered genus claims that encompass a wide array of compounds. The claims essentially encompass any inhibitor of the COTL1 protein or any inhibitor of the gene encoding COTL1 which are not described by their function, structure or relation thereto. For instance, a peptide, a compound and a natural product that specifically binds to COTL1 encompasses a vast variety of potential inhibitors that are not clearly defined by any particular structure. The genus for an inhibitor of the COTL1 protein or an inhibitor of the gene encoding COTL1 is highly variant, inclusive to numerous structural variants because a significant number of structural differences between genus members is permitted.
The specification describes:
“the COTL1 inhibitor is an agent that inhibits the expression or activity of the COTL1 protein or the gene encoding the same” (0087 of published application) and
“inhibitor may be selected from the group consisting of antisense nucleotides complementarily binding to COTL1 mRNA, small interfering RNA (siRNA), and
short hairpin RNA (shRNA), or may be selected from the group consisting of antibodies, peptides, aptamers, compounds, and natural products specifically binding to COTL1, but is not limited thereto” (0088 of published application).
The specification does not disclose the diverse genus for an inhibitor of the COTL1 protein or an inhibitor of the gene encoding COTL1. Additionally, the specification does not place any structure, chemical or functional limitations on the embraced by genera of “an inhibitor of the COTL1 protein or an inhibitor of the gene encoding COTL1”. The specification instead states the “COTL1 inhibitor is an agent that inhibits the expression or activity of the COTL1 protein or the gene encoding the same” (0087 of published application). This description does not convey a common structure or function. In sum, specification and the claims do not provide any guidance on the structure of either an “an inhibitor of the COTL1 protein or an inhibitor of the gene encoding COTL1”. Although, there is list of potential categories of inhibitors in the specification there is no description of structure, chemical or functional characteristics of any of these categories of inhibitors.
The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claims are broad generics, with respect to all of the potential species of inhibitors that may exhibit one, all, of or any of the claimed activity. The possible variations of compounds are limitless with potentially thousands of compounds that may exhibit the claimed activities. 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 claimed by them. 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. Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
The specification lacks sufficient variety of species of compounds to reflect this variance in the genus since the specification does not provide any examples of such a genus of compounds. Accordingly, the specification fails to provide adequate written description for the genera of “an inhibitor of the COTL1 protein or an inhibitor of the gene encoding COTL1 selected from the group consisting of antisense nucleotides complementarily binding to COTL1 mRNA, small interfering RNA (siRNA), short hairpin RNA (shRNA), antibodies, peptides, aptamers, compounds, and natural products specifically binding to COTL1” 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. Moreover, the specification neither describes the complete structure of a representative number of species, nor describes a representative number of species in terms of partial structure and relevant identifying characteristics. Absent of such teachings and guidance as to the structure and function of these compounds, the specification does not describe the claimed antagonist in such full, clear, concise and exact terms so as to indicate that Applicant had possession of all substances capable of being an expression promotor or activator of COTL1 at the time of filing of the present application. Thus, the written description requirement has not been satisfied.
Claims 9, 10 and 23 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 claims 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 specification describes that osteoclast differentiation activity is inhibited in osteoclasts isolated from COTL1 knock-out mice compared to normal mice, that the COTL1 knock-out mice had differences in bone structure compared to normal mice (Examples 1 and 2). The specification also describes that inhibiting COTL1 expression in isolated chondrocytes from cartilage increases the expression of COX-2, MMP-3 and MMP-13, osteoarthritis inducing factors (Example 3). The specification does not reasonably provide enablement for a method of treating a subject to inhibit osteoclast differentiation activity or to promote the expression of the osteoarthritis inducing factors, COX-2, MMP-3 and MMP-13 by administering a composition comprising an inhibitor of a COTL1 protein or gene encoding the same as an active ingredient to the subject in need of inhibiting osteoclast differentiation activity, or promoting the expression of the osteoarthritis inducing factors, COX-2, MMP-3 and MMP-13, respectively.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, the enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to methods of inhibiting osteoclast differentiation activity or promoting the expression of the osteoarthritis inducing factors, COX-2, MMP-3 and MMP-13 by administering a composition comprising inhibitor of COTL1 protein or a gene encoding COTL1 selected from the group consisting of antisense nucleotides complementarily binding to COTL1 mRNA, small interfering RNA (siRNA), short hairpin RNA (shRNA), antibodies, peptides, aptamers, compounds, and natural products specifically binding to COTL1 as an active ingredient to a subject in need of one of the conditions. Thus, the claims taken together with the specification imply that osteoclast differentiation activity can be inhibited or the expression of the osteoarthritis inducing factors, COX-2, MMP-3 and MMP-13 can be promoted in any subject in need thereof by administering in any amount or dosage a composition containing any concentration and formulation of any inhibitor of the COTL1 protein or any gene encoding COTL1 that is selected from the group consisting of antisense nucleotides complementarily binding to COTL1 mRNA, small interfering RNA (siRNA), short hairpin RNA (shRNA), antibodies, peptides, aptamers, compounds, and natural products specifically binding to COTL1.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
There appears to be no description in the prior art for the claimed methods. Ouyang et al. (CN 110066866) (ref. of record) reports that elevated COTL1 suggests osteoarthritis of a certain type and that COTL1 levels can be used for diagnosing the type of osteoarthritis (background and summary of invention of EPO translation). Jeong et al. (KR 10-197076 B1) (ref. of record) discloses a method of treating blood diseases by administering COTL1 protein or gene encoding for it (abstract and summary of invention). Xia et al. (Oncogene, 2018) (ref. of record) reports that COTL1 expression sensitizes breast cancer cells to chemotherapeutic drugs (abstract). Thus, as the state of the art stands, the method would be unpredictable depending on the subject and their condition and the substance being used to act as an expression promoter or activator of COTL1.
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The instant specification does not provide any working examples or animal models and does not provide any guidance for the instantly claimed method other than suggesting that osteosclerosis or osteoarthritis can be prevented or treated in a subject by administering a pharmaceutical composition or a health functional food containing a COTL1 protein or gene encoding the same or an expression promoter or activator of COTL1, based on observations made in COTL1 knockout mice and the expression of osteoarthritis inducing factors when COTL1 is inhibited in isolated chondrocytes (0038 and 0083-0085 of published application). The specification provides evidence that the down regulation of the COTL1 protein inhibits the differentiation activity of osteoclasts which reinforces bone density and increases the factors, COX-2, MMP-3 and MMP-13, that induce articular inflammation and cartilage degeneration (abstract and Examples 1-3). In addition, the specification reports that the differentiation activity of osteoclasts is reduced when the expression of the COTL1 protein or gene is reduced which results in increase bone density and the expression of Cox-2, MMP-3 and MMP-13 (0060).
Specifically, Example 1 discloses that osteoclast differentiation activity is inhibited in COTL1 knock-out mice as shown by reduced TRAP activity in osteoclasts isolated from the COTL1 knock-out mice compared to normal mice. Example 2 discloses that the bone density of COTL1 knock-out mice had higher bone mineral density and increased density of bone microstructures compared to normal mice. In addition, the COTL1 knock-out mice had increased % bone volume and trabecular number compared to normal mice, and low trabecular spacing compared to normal mice. Example 3 discloses that inhibiting COTL1 expression in isolated chondrocytes from cartilage increases the expression of COX-2, MMP-3 and MMP-13, osteoarthritis inducing factors.
Based on these observations, it appears that applicant is speculating that osteoclast differentiation activity can be decreased in a subject, and the osteoarthritis inducing factors, COX-2, MMP-3 and MMP-13, can be increased in a subject by inhibiting COTL1 protein or COTL1 gene expression in the subject (0110-0118 of published specification). This does not prove enablement for inhibiting of osteoclast differentiation activity or the increasing of the expression of COX-2, MMP-3 and MMP-13 in a subject. Observations in a COTL1 knockout mouse and a chondrocyte cell culture does not reasonably predict that the claimed method would be effective, since there is nothing in the disclosure that shows that by inhibiting COTL1 protein or COTL1 gene expression in a subject results in inhibition of osteoclast differentiation activity, and the promotion of the expression of COX-2, MMP-3 and MMP-13. There is nothing of record that shows inhibiting COTL1 in the subject would actually result in any of these claimed effects.
The specification does not describe what amount of the pharmaceutical composition would be required for achieving the claimed results. There general directions on determining the effective dose and a description of factors that would change the effective dose such as the purpose of use, the age, sex, weight, health status of the patient, etc., but no clear suggested dosages or working examples for inhibiting osteoclast differentiation activity, increasing bone density, or promoting COX-2, MMP-3 and MMP-13 expression with the claimed substances (0097-0098 of published application).
There is no detailed description or examples in the specification for the administration of a pharmaceutical composition comprising an inhibitor of the COTL1 protein or the gene encoding COTL1 for inhibiting osteoclast differentiation activity or promoting COX-2, MMP-3 and MMP-13 expression in a subject. There is no description of the required dosage or amount of the pharmaceutical composition to be administered and no description of the mode of administration of the pharmaceutical composition.
Therefore, there is no conclusive evidence in the instant disclosure to indicate that the instantly claimed methods can be used to inhibit osteoclast differentiation activity or promote COX-2, MMP-3 and MMP-13 expression in a subject.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to use the claimed invention as instantly claimed. Therefore, the claims are rejected under 35 U.S.C. 112, first paragraph, for a lack of enablement.
Response to Arguments
Applicant's arguments filed May 6, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 112 (a) written description, Applicant argues that claims 9, 10 and 23 have been amended to limit the COTL1 inhibitor to the specific representative classes: antisense nucleotides complementarily binding to COTL1 mRNA, small interfering RNA (siRNA), short hairpin RNA (shRNA), antibodies, peptides, aptamers, compounds, and natural products specifically binding to COTL1 (Remarks pg. 4 para. 2-3). Applicant argues that these classes are not a “highly variant” or structureless genus and are instead a closed group of well-recognized modalities for inhibiting a known target protein/gene. The Applicant further argues the specification defines the inhibitor functionally as “an agent that inhibits the expression or activity of the COTL1 protein or the gene encoding the same” and provides the exact representative species and the disclosure satisfies the written description (Remarks pg. 4 para. 4-5). However, these arguments were not found to be persuasive, since the specification does not describe how the inhibitor function to inhibit the expression or activity of the COTL1 protein or the gene and/or the corresponding structure that permits the inhibitor to have this function. An agent that inhibits is not sufficient description of how it functions to perform this task. As stated in the rejection, the claims essentially encompass any inhibitor of the COTL1 protein or any inhibitor of the gene encoding COTL1 which are not described by their function, structure or relation thereto. For instance, a peptide, a compound and a natural product that specifically binds to COTL1 encompasses a vast variety of potential inhibitors that are not clearly defined by any particular structure.
Applicant argues that the specification identifies the precise target, COTL1, provides multiple distinct classes of inhibitors that achieve the required inhibitory function, and demonstrates through examples showing that inhibition of COTL1 produces the exact therapeutic effects recited in the claims (Remarks pg. 4 last para.). However, this argument was not found to be persuasive, since the classes of inhibitors, themselves are not well-defined. There are no structures of a representative number of species of any of the claimed categories of inhibitors (antisense nucleotides complementarily binding to COTL1 mRNA, siRNA, shRNA, antibodies, peptides, aptamers, compounds, and natural products specifically binding to COTL1), and no description of a representative number of species in terms of partial structure and relevant identifying characteristics.
With respect to the rejections under 35 U.S.C. § 112 (a) enablement, Applicant argues that the specification provides sufficient guidance to enable the claimed methods with undue experimentation (Remarks pg. 7-8 bridging para.). Applicant further argues that the claims are directed to straightforward in vivo methods of using known classes of target-specific inhibitors that are limited to eight classes that are described in the specification and achieve well-defined biological effects (Remarks pg. 8 first para.). However, these arguments were not found to be persuasive, and it is maintained that the specification only provides general guidance on factors that inhibit the COTL1 protein, dose and a description of factors that would change the effective dose such as the purpose of use, the age, sex, weight, health status of the patient. There is no clear description of suggested dosages or working examples for inhibiting osteoclast differentiation activity, increasing bone density, or promoting COX-2, MMP-3 and MMP-13 expression with the claimed substances which are also not clear defined.
Applicant argues that the art is highly predictable, the level of skill is high and that the design and use of siRNA, shRNA, antisense oligonucleotides, antibodies, peptides, aptamers, and small-molecule compounds to inhibit a known gene/protein is routine (Remarks pg. 8 para. 2). Specifically, Applicant argues that Liao demonstrates that inhibition of COTL1 expression using siRNA in lung cancer cells is previously reported and well known in the art (Remarks pg. 8 para. 3). Applicant argues that Wang demonstrates that the impact of COTL1 on monocyte differentiation and using shRNA or siRNA for inhibition during the experimental process (Remarks pg. 8 para. 4). Applicant argues that Xia demonstrates various methods for knockdown/inhibition of COTL1 in breast cancer cells (Remarks pg. 8 para. 5). However, these arguments were not found to be persuasive, since the references appear to focus on specific inhibitors and different tissue types. Xia is directed to studying the mechanism of COTL1 in breast cancer by both knocking-out and over-expressing the COTL1 gene in cancer cells in culture. Xia does not provide any studies in a subject where there is administration of inhibitor of COTL1 protein or gene. In addition, the Liao and Wang references cited were considered to the extent argued but will not appear to any issued patent since it was not submitted in a proper information disclosure statement.
Applicant argues that the specification provides explicit definitions and representative species of inhibitors, detailed guidance of pharmaceutical compositions, carriers, dosages ranges, routes of administration and formulations suitable for humans and animal use on pg. 16-18 (Remarks pg. 8 para. 6). However, this argument was not found to be persuasive and it is maintained that the specification only provides general directions on determining the effective dose and a description of factors that would change the effective dose such as the purpose of use, the age, sex, weight, health status of the patient, etc., and does not provide clear suggested dosages or working examples for inhibiting osteoclast differentiation activity or promoting COX-2, MMP-3 and MMP-13 expression with the claimed substances (0097-0098 of published application).
Applicant argues that Examples 1-3 provide genetic knockout of COTL1 data which is a direct functional equivalent of the claimed inhibitors produces the claimed effects osteoclast differentiation, increases bone density, increases osteoarthritis inducing factor expression. Applicant further argues that this data in combination with routine optimization of dosage and formulation fully enables the claims (Remarks pg. 8-9 bridging para.). However, these arguments were not found to be persuasive, since a knockout mouse is not a direct functional equivalent of the claimed inhibitors. Knocking out a gene in a mouse does not demonstrate how a siRNA, shRNA, antisense oligonucleotides, antibodies, peptides, aptamers, and small-molecule compounds would behave in a subject. At best it suggests how this wide variety of categories of potential inhibitors might effect a subject once administered, but it does not provide evidence that inhibition of the COTL1 protein or gene using one of these potential inhibitors would have the same effect as a complete knockout of the gene.
Applicant argues that any remaining experimentation would be routine and not undue, since the specification’s detailed guidance and working models provide sufficient guidance eliminating undue experimentation. Applicant further argues that it is not required to provide working examples of every embodiment when there is clear guidance (Remarks pg. 9 para. 2). However, these arguments were not found to be persuasive, since no working models have been provided showing treatment of a subject whether in an animal model or human. It is maintained that no evidence has been provided that the claimed methods involving the administration of a composition containing an inhibitor of COTL1 protein or gene would inhibit osteoclast differentiation activity, increase bone density or promote expression of osteoarthritis inducing factors in a subject. The specification provides general directions on determining the effective dose and a description of factors that would change the effective dose such as the purpose of use, the age, sex, weight, health status of the patient, etc., but does not clear suggested dosages or working examples for inhibiting osteoclast differentiation activity or promoting COX-2, MMP-3 and MMP-13 expression with the claimed substances (0097-0098 of published application).
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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