DETAILED ACTION
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 .
Priority
This Application is a National Stage Entry under U.S.C. § 371 of PCT/ES2020/070104 filed 02/14/2020. Applicant’s claim to priority from foreign application ESP201930118 dated 02/15/2019 is hereby acknowledged.
Application Status
Amendments to claims filed 12/04/2025 are hereby acknowledged. Claims 17 and 32 are currently amended. Claims 33-35 are newly added. Claims 9, 12, 15-16, 18-19 and 21-31 are cancelled. Claims 1-8, 10-11, 13-14, 17, 20 and 32-35 are pending. However, claims 1-8, 10-11, 13-14 and 20 are withdrawn from consideration since they are drawn to unelected inventions.
Claims 17 and 32-35 are under examination in this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/04/2025 was filed after the mailing date of the Office Action on 06/04/2025 and is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
Replacement sheet for Figure 10 filed 12/04/2025 is hereby acknowledged and is acceptable.
The following rejections are modified as necessitated by Applicant’s amendments, but are maintained from Office Action dated 06/04/2025:
Claim Rejections - 35 USC § 112(a)
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.
Enablement Rejection
Claims 17 and 32-35 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.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
The nature of the invention;
The breadth of the claims;
The state of the prior art;
The level of skill in the art;
The level of predictability in the art;
The amount of direction provided by the inventor;
The presence or absence of working examples;
The quantity of experimentation necessarily needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
Further MPEP §2164.01(c) recites, “When a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation. See In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991) (claiming a chimeric gene capable of being expressed in any cyanobacterium and thus defining the claimed gene by its use).”
The relevant In re Wands factors are applied to Claims 1 and 7 are as follows:
Nature of the Invention and Breath of the claims
Claim 17 recites: “ [A] method for treating obesity, comprising administering a pharmaceutical composition comprising at least one functionalized nanosystem for transporting biologically active molecule to a subject in need thereof, wherein the nanosystem comprises:
A biologically active molecule which is a mir_21 microRNA; and
A pharmaceutically acceptable carrier comprising a nanoparticle and a transporter molecule capable of linking oligonucleotides, wherein:
the biologically active molecule and the nanoparticle are bound to the transporter molecule independently;
the nanoparticle comprises a cationic gold core; and
the transporter molecule is a Gemini cationic surfactant comprising Gemini surfactant 16-3-16 or Gemini surfactant 16-Ph-16.”
With respect to claim breadth, the standard under 35 U.S.C. §112(a) entails determining what the claims recite and what the claims mean as a whole. The nature of the invention indicates that the instant claims encompass a method for treating obesity, comprising administering a pharmaceutical composition comprising at least one functionalized nanosystem for transporting biologically active molecule to a subject in need thereof, wherein the nanosystem comprises miR-21 microRNA and a carrier that is a Gemini cationic surfactant.
While the claims are directed to a method of treating obesity in any subject in need thereof, the specification discloses only the method in mice. Therefore, for the enablement determination, claims are evaluated in light of the specification whether the claimed invention is enables for a method of treating obesity in mice.
State of the Art
A review of the art and prior art shows that the following are challenges associated with the use of miR-21 microRNA :
In adipocytes and adipogenesis:
According to Kim (Kim, Y.J. et al. “ MicroRNA 21 regulates the proliferation of
human adipose tissue-derived mesenchymal stem cells and high-fat diet-induced obesity alters microRNA 21 expression in white adipose tissue”. Cellular Physiology, Vol. 227 (2012), pp: 183-193), miR-21 increases adipogenic differentiation of adipose tissue-derived mesenchymal stem cells (see page 184, left column, lines 26-29).
According to Kang (Kang, M. et al. “Role of microRNA-21 in regulating 3T3-L1 adipocyte differentiation and adiponectin expression”. Molecular Biology Reports, Vol. 40 (2013), pp: 5027-5034), miR-21 is overexpressed in adipocyte during differentiation and contribute to lipid accumulation, enlargement of adipocytes, therefore enhancing differentiation (see page 5029, left column, “[R]esults” section first and second paragraphs).
Scheideler (Scheideler, M. “MicroRNAs in adipocyte formation and obesity”, Best Practice & Research Clinical Endocrinology & Metabolism, Vol. 30 (2016), pp: 653-664) reviews the findings in the prior art about the roles of microRNAs in adipocyte and obesity, up to until 2016, and confirms the role of miR-21 as a pro-adipogenic microRNA (see page 655, third paragraph and Table 1).
In Obesity development and treatment:
Kim (cited above) also teaches that miR-21 is upregulated in high-fat diet induced obesity (page 184, left column, lines 29-33; page 185, right column, paragraph “[C]hanges in miR-21 levels in the white adipose tissues of mice during obesity development).
Seeger (Seeger, T. et al. “Long-term inhibition of miR-21 leads to reduction of obesity in db/db mice”. Obesity, Vol. 22 (2014), pp: 2352-2360) teaches that using a LNA anti-miR-21 oligonucleotide is favorable to decrease in body weight, in adipocyte sizes, in pericardial fat, and reduces the serum levels of triglycerides and cholesterol in the mice subjected to high-fat diet for obesity inducing (see Figure 3). Seeger specifically teaches weight loss induced by miR-21 inhibition (see page 2354, right column). Seeger teaches that weight loss induced my miR-21 knockdown is accompanied with changes in adipokines in white adipose tissue as well (id).
The level of Predictability in the art/ the level of skills in the art
While Seeger makes it clear that using a miR-21 in a composition with a carrier as a method of treating obesity in mice is not possible, since Seeger uses an anti-miR-21, a LNA antagonist oligonucleotide to treat obesity in mice, Seeger only used a limited number of mice to perform the experiment (LNA-21 n=5; LNA control n=3; untreated n= 3; see page 2353, “[M]ethods” section, first paragraph).
Seeger is using the LNA-modified anti-miR-21 over long-term, i.e. weekly administration for 18 weeks (see page 2353, “[M]ethods” section, first paragraph and “[R]esults” section, first paragraph).
The level of skills in the art is high, given the fact that animal husbandry (e.g. feeding, handling) is widely used and established in prior art, injection of oligonucleotides for knock-out studies is common in the art, mouse model experimentation is also common in the art.
The unpredictability therefore here in Seeger resides in the low number of animal tested. However, supported by in vitro data taught by Kim, Kang and Scheideler, all evidences point to a role for miR-21 as a pro-adipogenic microRNA and counteracting its role being beneficial in the treatment of obesity.
The amount of direction provided by the inventor and presence or absence of working examples
What is described in the specification are working examples, testing the toxicity of treatment in example 3, using mice, with an unknown number of duplicates, with results shown in Table 2a and 2b after 7 days or after 15 and 30 days respectively. The results here show no change in the weight of treated mice.
Table 3a shows toxicity studies of compositions comprising miR-21 on blood cells, hemoglobin levels, on an unknown number of mice, with only reference group with a known number n=4.
Next, Applicant shows accumulation of particles from different formulations in liver and lung tissues of treated mice after 48 hours of treatment (Figures 7 and 9). Figure 8 shows experimentation using 2 formulations comprising miR-21 and their effect on organs, wherein Applicant points to appearance of beige adipose tissue in adipose tissue of treated mice.
In Figure 10, and example 4, Applicant shows studies of the effect on in vivo treatment of the composition comprising miR-21 on weight and fat gain in a mouse model subjected to high fat diet. Applicant uses 2 compositions comprising gold particles and Gemini surfactant, i.e. Au@16-Ph-16-miR-21 and Au@16-3-16-miR-21.
In Figure 10, Applicant shows that compared to control (n=6), animal treated with the composition (n=9 in each group), present with body weight loss.
In Figure 11, Applicant presents the effects of treatment stating that the white adipose tissue is transformed into beige adipose tissue under both compositions type.
In Figures 12-14, Applicant presents data on the effect of the two different compositions in different amount (0.2 µg versus 0.3 µg) on the expression of beige adipocyte, white adipocyte and thermogenesis markers.
There is a significant amount of examples and data presented by Applicant. However, all the data are the contrary of data found in the prior art.
The quantity of experimentation necessary
Since Applicant’s data are the reverse presented in the prior art, one with ordinary skills in art would have to reconsider all basis for each experimentation:
Whether miRNA-21 is really adipogenic or anti-adipogenic,
Whether the nanosystem/carrier composition needs to be exact to replicate the effects,
Whether the number of samples are adequate,
Whether the formulations Au@16-ph-16-miR-21 or Au@16-3-1-miR-21 are representative of the naturally occurring miR-21 in their effects on adipocytes,
Whether all Gemini cationic surfactants will have the same effect,
Whether the timing of administration and/or observation is appropriate,
Whether there is only some residues and modifications in miR-21 responsible of the effect,
Whether the composition/carrier induces a conformation in a loop that leads the composition to act as an anti-miR-21.
Applicant did not provide any guidance for these aspects cited above. Without such guidance, it would be difficult for one with ordinary skills in the art to reproduce the claimed invention.
Conclusion
Altogether, the Specification does not enable for a method of treating obesity using miR-21 within a nanosystem, and a carrier made of a transporter molecule that is a Gemini cationic surfactant. The transporter molecule is not the bioactive molecule in the composition, thus the composition relies upon the action of miR-21. In the prior art, it was demonstrated that miR-21 is negative for treating obesity, and that an anti-miR-21 is beneficial for treating obesity.
Claims 17 and its dependent claims 32-35 are therefore rejected for lack of enablement under 35 U.S.C.§ 112(a).
Response to Arguments
Applicant's arguments filed 12/04/2025 have been fully considered but they are not persuasive.
Applicant arguments in Remarks, page 8, seems to revolve around the reference Seeger et al., stating “Given that the studies in Seeger involved db/db mice, it cannot be concluded that the results disclosed in the present application using normal mice are contrary to the results in this reference—it is tantamount to an apples-to-oranges comparison”.
In response, Examiner would like to remind that the state of the art presented in the rejections is a combination of multiple references: Kim, Kang and Scheideler, all present evidence pointing to a role for miR-21 as a pro-adipogenic microRNA. These teachings are against its role being beneficial in the treatment of obesity.
Regarding the reference presented by Applicant supporting the instant application, Girádez-Pérez et al. present data from Applicant’s own NPL.
The data could be explained by prior art such as Kohl (Kohl, Y. et al. "Effect of gold nanoparticles on adipogenic differentiation of human mesenchymal stem cells”. Journal of Nanoparticle Research, Vol. 13 (2011), pp: 6789-6803) and Chen (Chen, H. et al. "In vivo study of spherical Gold nanoparticles: inflammatory effects and distribution in mice". PLOS One, Vol. 8, no. 2 (2013), p: e58208). Both Kohl and Chen teaches that the gold nanoparticles themselves have anti-inflammatory and anti-adipogenic properties.
Xue (Xue, T. et al. "Browning of white adipocytes by gold nanocluster mediated electromagnetic induction heating hyperthermia". Nanoscale, Vol. 14 (2022), p: 1187) also teaches that gold nanoparticles can be used as an adjuvant to electromagnetic induction heating hyperthermia as a combination therapy against obesity.
The Gemini surfactant themselves have been developed as a delivery vehicle more than twenty years ago, as taught by Hait (Hait, S.K. et al. "Gemini surfactants: a distinct class of self-assembling molecules". Current Science, Vol. 82, No.9 (2002), pp: 1101-1111), with antimicrobial properties described (see page 1108, left column).
The result of analysis of the prior art leans towards an effect of the gold nanoparticles, themselves, preventing adipocyte differentiation and inducing browning of adipocytes and thermogenesis. Other references concerning miR-21 teach the opposite effect for miR-21.
Therefore the rejections are maintained.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636