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 .
Drawings
The drawings are objected to under 37 CFR 1.83(a). The drawings must show every feature of the invention specified in the claims. Therefore, the limitation “... the delivery device contacts one or more layers of epidermis with one or more reversible permeability enhancers...” of claim 1; the limitation “the one or more bioactive agents moves or diffuses deeper through the epidermis through a basal layer of the epidermis and into at least a portion of underlying viable dermis to achieve an uptake of a portion of the one or more bioactive agents by one or more susceptible blood capillary plexus or lymphatic capillary plexus” of the claim 1; the limitation “wherein after administration and uptake, the one or more bioactive agents circulates through the blood vasculature or lymphatic vasculature to one or more tumors” of the claim 1 must be shown or the feature(s) canceled from the claim(s). No new matter should be entered.
Note: applicant is requested to show that the delivery device, i.e., needle contacts or inserts into an epidermis layer, and the bioactive agents moves/diffuses through the epidermis through a basal layer of the epidermis and into at least portion of underlying viable dermis.
The Figs. 1-2B shows the structure of the skin layers but does not show that the needle being inserted into the epidermis layer, and the bioactive agent moves/diffuses through the epidermis through at least portion of underlying viable dermis. In addition, the Figs. 9A-9B are blurry. Examiner makes a guessing that the Figs. 9A-9B show as a cancer tumor, but they do not show the claimed subject matter, as required in the claimed invention.
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.
112 6th Acknowledgement
With regard to Applicant’s “means for controlling the administration flow rate including at least one component” and the limitation “means for penetrating at least a most superficial layer of the epidermis” of claim 8, the language appears to be an attempt to invoke 35 USC 112, 6th paragraph interpretation of the claims. A claim limitation will be interpreted to invoke 35 U.S.C. 112, sixth paragraph, if it meets the following 3-prong analysis:
(A) the claim limitations must use the phrase “means for ” or “step for; ”
(B) the “means for ” or “step for ” must be modified by functional language;
and
(C) the phrase “means for ” or “step for ” must not be modified by sufficient structure, material or acts for achieving the specified function.
In the instant case, applicant appears to have met the limitations set forth in MPEP § 2181, and examiner has turned to the specification for clarification.
In the specification, applicant defines the “means for controlling the administration flow rate including at least one component” is equivalent to a pump, a fluid delivery rate controller, a syringe, a pen, an elastomer membrane.... Applicant defines the “means for penetrating at least a most superficial layer of the epidermis” as a needle.
Accordingly, the examiner is interpreting the “means for controlling the administration flow rate including at least one component” is equivalent to a pump, a fluid delivery rate controller, a syringe, a pen, an elastomer membrane.... And the limitation “means for penetrating at least a most superficial layer of the epidermis” is interpreted to encompass a needle and its equivalents. Equivalent structures may include those that perform the function specified in the claim, structures that are not excluded by any specific definition provided in the specification for an equivalent, or is a structural equivalent of the corresponding element disclosed in the specification. See MPEP 2183.
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 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.
Claims 1-11, 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Pettis et al. (US 2005/0180952).
Regarding claims 1 & 13, Pettis discloses a method of treating a subject with a disease comprising one or more tumors by administering one or more bioactive agents to the one or more cancers, i.e., tumors, lymph nodes, para [0017, 0035-0037] comprising:
(a) applying one or more delivery devices having between 2 and 50,000 delivery structures, (e.g. multiple microneedle arrays, para [0080], therefore, the delivery device or the needle having more than 2 or in the requirement ranges between 2 to 50,000 delivery structures) to one or more sites of a skin of a subject comprising blood vasculature and lymphatic vasculature, (see abstract, paras [0002 & 0031]),
wherein the delivery device contacts one or more layers of epidermis (e.g. the formulations are delivered at a targeted depth just under the stratum corneum and encompassing the epidermis and upper dermis, para [0082]) with one or more reversible permeability enhancers comprising: electrical permeability enhancer that induces reversible increase in the permeability of one or more barrier cells of the epidemic to at least one or more bioactive agents (e.g. the microneedle array being used to delivery bioactive agents by electric field, such as iontophoresis, para [0078]).
Pettis also states in the Back Ground of the Invention that it is well-known in the art to delivery drug with rely upon a chemical permeability enhancer (chemical mediators, para [0003]) or physical permeability enhancer (hydrophobic adsorption, para [0004]) or electrical permeability enhancer (e.g. the microneedle array being used to delivery bioactive agents by electric field, such as iontophoresis, paras [0003], sonophoresis, para [0003], electroporation, para [0003]) that induces a reversible increase in the permeability of one or more barrier cells of the epidermis to at least one or more bioactive agents (para [0002]);
Note: The limitation... that induces a reversible increase in the permeability of one or more barrier cells of the epidermis to at least one bioactive agent is the result of using a delivery device (such as a microneedle array or needle device) inserted into one or more layers of the epidermis in combination with one or more reversible permeability enhancers. Therefore, Pettis discloses all the claimed subject matter discussed in step a) above.
(b) Administering a total liquid dosage (the total amount of an injection) involves delivering at least two sub-doses—within a range of 2 to 50,000 sub-doses—of one or more bioactive agents at a controlled administration flow rate through a delivery device (see paragraphs [0019–0021, 0090–0091]). For example, each microneedle array holds at least one small sub-dose. The total liquid dosage equals the sum of each sub-dose contained across the microneedle arrays. These arrays are designed for insertion into one or more sites of the lymphatic vasculature (e.g., to treat lymphadenitis). Ultimately, the microneedle array increases the delivery rate and the volume of the agent delivered within a given timeframe compared to a single-needle injection.
wherein each sub-dose of the one or more bioactive agents is independently administered, in an administering step, to a plurality of independent depths within the epidermis prior to any subsequent diffusion or movement of the one or more bioactive agents within the epidermis (see para [0082], the formulations are delivered at a targeted depth just under the stratum corneum and compassing the epidermis and upper dermis);
Note: each of the microneedle arrays holds at least one sub-dose of the bioactive agent. Therefore, wherein each sub-dose of the one or more bioactive agents is independently administered to a plurality of independent depths within the epidermis prior to any subsequent diffusion or movement of the one or more bioactive agents within the epidermis.
wherein the plurality of independent depths within the epidermis is from about 1 µm to about 500 µm (as supported by para [0082], the formulations are delivered at a target depth of 0.025-2.5mm = 25-2500 µm), beyond a most superficial surface layer of epidermis of the subject, but still within the epidermis of the subject (as supported by para [0082], the formulations are delivered at a targeted depth just under the stratum corneum and encompassing the epidermis and upper dermis), and
Regarding the limitation wherein, following administration, one or more bioactive agents moves or diffuse deeper through the basal layer of the epidermis and into a portion of the underlying viable dermis to achieve an uptake of a portion of the one or more bioactive agents by one or more susceptible blood capillary plexus or lymphatic capillary plexus, this is a functional limitation or inherent result of administering 2 to 50,000 sub-doses of the bioactive agent(s) at an insertion depth ranging from 0.025 to 2.5 mm (25 to 2500 µm, see para [0082]), which falls within the required range of 1 to about 500 µm) beyond the most superficial surface layer of the subject's epidermis. It is noted that when the bioactive agent is delivered at a target depth, it does not stay within the target area; instead, it diffuses deeper through the basal layer of the epidermis and into at least a portion of the underlying viable dermis.
Nevertheless, Pettis discloses the administration of 2 to 50,000 sub-doses of bioactive agent(s) with an insertion depth ranging from 0.025 to 2.5 mm (25 to 2500 µm), which falls within the required range of 1 to 500 µm, beyond the superficial surface layer of the epidermis.
Therefore, Pettis clearly discloses the required limitations—specifically, that following administration, the bioactive agent(s) move or diffuse deeper through the basal layer of the epidermis and into at least a portion of the underlying viable dermis (para [0021]), achieving uptake by the lymphatic capillary plexus.
Regarding the limitation: wherein after administration and uptake, the one or more bioactive agents circulates through the blood vasculature or lymphatic vasculature to one or more tumors, para [0015, 0024,0055, 0059, 0067]; wherein a greater concentration of the one or more bioactive agents is delivered to the one or more tumors compared to intravenous, intradermal, or subcutaneous delivery using an identical one or more bioactive agents. It is noted that this limitation above is considered as a functional limitation. This is a direct result of delivering the one or more bioactive agents using a delivery device having between 2 and 50,000 delivery/needle structures (such as a microneedle array).
In this case, Pettis discloses the same concept of using microneedle arrays (having between 2 and 50,000 delivery/needle structures) for delivering one or more bioactive agents in combination with one or more permeability enhancers (e.g., iontophoresis, sonophoresis, electroporation) into the epidermal tissue (as discussed above). Pettis states in paragraphs [0055-0065], and particularly in para [0056], that therapeutic agents delivered in accordance with the methods of the invention are transported in vivo through the local lymphatic system, into the systemic blood circulation, and into deeper tissue environments. (Note: As mentioned in paras [0057-0065], one or more tumors can be located in deeper or specific tissues). Furthermore, para [0059] states that the agent is first distributed with high bioavailability (greater concentration) to the lymphatic tissue local to the administration site, followed by a more widespread lymphatic delivery into the general circulation. In addition, the paras [0058-0065] states that: delivery of bioactive agents, particularly therapeutic agents have a higher tissue bioavailability (greater concentration) in a particular tissue (one or more tumors) as compared to when the agent is delivered by other route such as SC delivery, intramuscular delivery, intravenous delivery.
For the reasons stated above, following administration and uptake, the bioactive agents circulate to achieve high bioavailability within the lymphatic tissue local to the administration site. They then deliver more widespread lymphatic coverage into the general circulation, diffusing deeper through the epidermis, past the basal layer, into at least a portion of the underlying viable dermis, and ultimately reaching specific target tissues (e.g., one or more tumor areas), and a greater concentration of the one or more bioactive agents is/are delivered to the one or more tumors compared to intravenous, subcutaneous, intradermal (if using syringe with needle) delivery using an identical one or more bioactive agents.
Note: using microneedle array to deliver the agent at a targeted depth results in a larger amount of the bioactive agent reaching a specific tissue (e.g., lymphatic vasculature) compared to utilizing these other delivery methods, e.g., such as SC, intramuscular, intravenous delivery.
The claim requires comparison to intravenous, intradermal, or subcutaneous delivery (using an 'or' conjunction). In other words, if the prior art meets only one of these delivery methods—intravenous, intradermal, or subcutaneous—it satisfies the claim. In this case, Pettis compares it to two other delivery methods: intravenous and subcutaneous. Therefore, it meets the claimed invention
In addition, like microneedle array delivery, a standard needle and syringe is considered a form of intradermal delivery. As mentioned above, microneedles pierce the outer skin layer and deposit the active agent directly into the viable epidermis and upper dermis layers. Meanwhile, a standard needle is inserted at a shallow angle directly into the dermis layer of the skin. In other words, microneedles are significantly shorter than a standard needle. Therefore, a person skilled in the art would recognize that delivering one or more bioactive agents via microneedles will achieve greater delivery to the lymphatic vasculature compared to other intradermal methods, such as a standard needle and syringe.
Pettis does not disclose the limitation that wherein administration of one or more bioactive agents achieves a dermal interstitial fluid pressure in the underlying dermis beneath a site of administration of about 1 mmHg to about 15 mmHg.
Note: As discussed above, the microneedles are inserted into the epidermal compartment (above the dermis layer) at a certain pressure. However, when the bioactive agent is delivered to the target depth, it does not stay within the target area; instead, it diffuses deeper through the basal layer of the epidermis and into at least a portion of the underlying viable dermis. It should be noted that the fluid pressure during diffusion will decrease (in very small values in fluid pressure) compared to the fluid pressure in the epidermal compartment.
Thus, it would have been obvious to a person having ordinary skill in the art at the time the invention was made to determine the aforementioned values, since it has been held that discovering optimum values (e.g., 1 mmHg to about 15 mmHg) of a result-effective variable involves only routine skill in the art. For example, dermal interstitial fluid pressure depends on the specific skin characteristics of each patient (such as children, adults, males, females, or the elderly) and the amount of pressure or force applied during injection into the target epidermis. Additionally, when delivering drugs via a microneedle array (MNA) device, managing fluid pressure at the target area (the dermis or epidermis) provides critical therapeutic benefits; maintaining low pressure reduces pain, tissue damage, and uneven absorption. MNAs distribute the total fluid volume across dozens or hundreds of microchannels simultaneously. By spreading the volumetric flow rate across an array, the fluid velocity and localized pressure at each individual microneedle tip are substantially reduced, thereby preventing the sudden, intense tissue compaction responsible for injection pain.
Regarding claim 2, Pettis discloses all the subject matter claimed as required. Pettis discloses that wherein the total liquid dosage of the one or more bioactive agents administered to the plurality of independent depths, i.e. depths of an insertion of the plurality of independent microneedles, within the epidermis comprises administration to a depth within at least a portion of non-viable epidermis (e.g. formulations are delivered at a depth of 0.5mm-2.5mm = 500-2500µm, para [0082]; or inserting the tip of the needle into the skin to a depth of 1.5mm = 1500 µm, para [0084], which is outside of epidermis layer) and/or at least a portion of viable epidermis (e.g. the formulations are delivered at a depth just under the stratum corneum encompassing the epidermis and upper dermis, about 0.025-2.5mm = 25-2500 µm, para [0082]).
Note: the thickness of the epidermis is in between 75-150µm, para [0005]; or about 1-150 µm, as required in the claims 3, 5-6 of the current application. Thus, if the depth of the insertion in between 75-150 µm is within epidermis, i.e., viable epidermis. If the depth of the insertion is not in the range of 75-150 µm, then the depth of the insertion is within a portion of non-viable epidermis, i.e., stratum corneum or dermis or subcutaneous layer.
Regarding claim 3, Pettis discloses all the subject matter claimed as required. Pettis discloses that wherein the total liquid dosage of the one or more bioactive agents is administered to a plurality of depths within the epidermis consisting only of one or more viable epidermal layers (e.g., the formulations are delivered at a depth just under the stratum corneum encompassing the epidermis and upper dermis, about 0.025-2.5mm = 25-2500 µm, para [0082]) and not a non-viable epidermal layer, i.e., stratum corneum layer.
Regarding claim 4, Pettis discloses all the subject matter claimed as required. Pettis discloses that wherein the plurality of depths within the viable epidermis is from about 1 µm to about 250 µm (e.g., the formulations are delivered at a depth just under the stratum corneum encompassing the epidermis and upper dermis, about 0.025-2.5mm = 25-2500 µm, para [0082]) beyond the deepest non-viable epidermal layer (i.e., stratum corneum layer) but still within the viable epidermis.
Regarding claim 5, Pettis discloses all the subject matter claimed as required. Pettis discloses that wherein the average of the plurality of independent depths exhibits a combined average sub-dose delivery depth within the epidermis of about 70 pm to about 175 pm (e.g. the formulations are delivered at a depth just under the stratum corneum encompassing the epidermis and upper dermis, about 0.025-2.5mm = 25-2500 µm, para [0082]) beyond the most superficial surface layer of the epidermis.
Furthermore, it would have been obvious to one of ordinary skill in the art at the time of the invention to select a combined average sub-dose delivery depth within the epidermis of about 70–175 µm. It is well-established that discovering the optimum value of a result-effective variable requires nothing more than routine skill. This is particularly true given that epidermal thickness varies by patient and depends on whether the target treatment area is deep or shallow.
Regarding claim 6, Pettis discloses all the subject matter claimed as required. Pettis discloses a plurality of independent depths having a combined average depth of administration within the epidermis. For example, the formulations are delivered at a depth just under the stratum corneum, encompassing the epidermis and upper dermis (about 0.025–2.5 mm or 25–2,500 µm, paragraph [0082]). Within this configuration, each independently administered sub-dose is placed at a depth within the epidermis that is deeper, shallower, or the same relative to the others.
Furthermore, it would have been obvious to a person having ordinary skill in the art at the time the invention was made to determine the optimal parameter for a combined average sub-dose delivery depth within the epidermis. It is well-established that discovering the optimum value of a result-effective variable involves no more than routine skill in the art. For instance, the thickness of epidermal tissue varies by patient and depends on whether the target treatment area is deep or shallow.
Regarding claim 7, as best as understood, Pettis discloses all the subject matter claimed as required. Pettis also discloses that wherein a frequency of each of the independent sub-dose administration depths within the viable epidermal layer (at an insertion depth is about 0.025-2.5mm = 25-2500 µm, para [0082]) and/or a non-viable epidermal layer (at an insertion depth is 0.5mm-2.5mm = 500-2500µm, para [0082]; or at an insertion depth of 1.5mm = 1500 µm, para [0084]), which is outside of epidermis layer exhibits a Gaussian distribution (normal distribution of the microneedle array) of depths.
Regarding claim 8, Pettis discloses all the subject matter claimed as required. Pettis also discloses that wherein the delivery device comprises an array comprising between 2 and 50,000 of the delivery structures in fluid communication with the one or more bioactive agents in a liquid carrier vehicle,
wherein the delivery device comprises a means for controlling the administration flow rate including at least one component selected from the group consisting of a pump, a fluid delivery rate controller, a syringe (Fig. 10), a pen, an elastomer membrane, or any combination thereof, see para [0090];
wherein the delivery structures comprise a means. i.e. microneedles for penetrating at least a most superficial layer of the epidermis (at insertion depth of 0.025-2.5mm, para [0082]); and
wherein the one or more bioactive agents in the liquid carrier vehicle is delivered by the delivery structures to the plurality of independent depths within a viable epidermis of the subject, thereby administering between 2 and 50,000 sub-doses of the one or more bioactive agents.
Regarding claim 9, Pettis discloses all the subject matter claimed as required in the claims 1 & 8 above except for the limitation that a controlled administration flow rate of the bioactive agent of about 0.1 to 100 µl/hr per delivery structure of the delivery structures. It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a controlled administration flow rate of a bioactive agent ranging from 0.1 to 100 µl/hr per delivery structure, because optimizing a result-effective variable involves only routine skill. Specifically, the required flow rate depends on patient-specific factors such as age, gender, skin type, and the particular treatment protocol for specific disease being treated.
Regarding claim 10, Pettis discloses all the subject matter claimed as required in the claims 1 & 8 above. Pettis further discloses that wherein the delivery structures, i.e., microneedles comprise a standard, i.e., cylindrical in nature or nonstandard geometric shape, pyramidal, rectangular, octagonal, wedged, and other geometrical shapes para [0080].
Regarding claim 11, Pettis discloses all the claimed subject matter as required in the claim 1 above except the limitation that wherein the overall controlled administration flow rate of the one or more bioactive agents to the plurality of depths within the epidermis is from about 0.02 µl/hr/cm2 to about 50,000 µl/hr/cm2 based on the total surface area of a delivery device that is in contact with the skin of the subject.
It would have been obvious to a person having ordinary skill in the art at the time the invention was made to determine the aforementioned values. It has been established that optimizing the values of a result-effective variable, such as the flow rate (e.g., 0.02–50 µl/hr/cm²), requires nothing more than routine skill in the art. For example, the flow rate is based on the total surface area, which inherently depends on tumor size and the specific treatment conditions of a patient.
Regarding claim 14, Pettis discloses all the claimed subject matter as required in the claim 1 above. Pettis discloses that wherein the one or more bioactive agents is delivered to a tissue volume of the epidermis encompassing the one or more bioactive agents prior to any subsequent diffusion or movement of the one or more bioactive agents within the epidermis of about 0.7 mm3 to about 2,500 mm3 (e.g., the injection volume is nor more than 100µL = 100 mm3, para [0079], or 75 µL = 75 mm3, para [0255]).
In addition, it would have been obvious to a person having ordinary skill in the art at the time the invention was made to obtain the values above, as it has been held that discovering an optimum value of a result-effective variable involves only routine skill in the art. Furthermore, the treatment depends on each patient, such as the number of doses or the injection pressure and force applied to the target epidermis
Regarding claim 15, Pettis discloses all the claimed subject matter as required in the claim 1. Pettis discloses that wherein a concentration of the one or more bioactive agents within the one or more tumors is about 5-10 folds, para [0064] which is in the required ranges of 1.25-fold to about 50-fold more than intravenous, intradermal, or subcutaneous delivery of the one or more bioactive agents.
In addition, it would have been obvious to a person having ordinary skill in the art at the time the invention was made to determine the values above, because discovering such values (e.g., 1.25-fold to about 50-fold) for a result-effective variable involves only routine skill
Regarding claim 16, Pettis discloses all the claimed subject matter as required in the claim 1. Pettis discloses that wherein the bioactive agent is useful for retarding progression of, delaying onset of, prophylaxis of, amelioration of or reducing symptoms of the disease comprising the one or more tumors, paras [0038-0041].
Regarding claim 17, Pettis discloses all the claimed subject matter as required in the claim 1. Pettis discloses that wherein the one or more bioactive agents is continuously administered to a subject for a time period of about 10 mins, para [0089], which is in the ranges of 0.1 hours = 6 mins to about 96 hours. In addition, the Fig. 4 shows the treatment about 3hrs to 4wks, or the Fig. 5 shows the treatment about 1hr-5hrs.
Regarding claim 18, this limitation is being rejected using same analysis as noted above with regard to claim 1. Pettis further discloses that: following administration, the permeability of the one or more barrier cells returns to a state prior to contact of the epidermis with the one or more reversible permeability enhancers (e.g., Once the treatment or bioactive agent is applied to a targeted tissue and the microneedle array device is removed, the epidermal cells quickly return to their tightly closed state, restoring the skin's protective shield and allowing it to recover).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Pettis et al. (US 2005/0180952) in view of Ross (US 2013/0144257).
Pettis discloses all the claimed subject matter as required in the claim 1 above except for the limitation the physical permeability enhancers (of the microneedle arrays) comprises a nanostructured or nanotopography surface.
Ross discloses a microneedle transdermal device 10 comprising: a microneedle arrays 12/22 with permeability enhancer (e.g. the microneedle array being used by electric field, such as iontophoresis for delivering bioactive agents); wherein the physical permeability enhancers comprise a nanostructured or nanotopography surface 26, see abstract, Fig. 3.
t would have been obvious at the time the invention was made to a person having ordinary skill in the art to modify the microneedle device of Pettis by providing a physical permeability enhancer with a nanostructured or nanotopographical surface, as taught by Ross, to allow the surface of the microneedle to interact with the cells of the dermal barrier and improve the efficiency of delivery and uptake of the bioactive agents, as described in paragraph [0071] of Ross.
Response to Arguments
Applicant's arguments filed 08/27/26 have been fully considered but they are not persuasive.
1) Applicant argues that Pettis administers to the dermis, not to the Epidermis.
In response, Pettis clearly states in para [0082] that: ... The actual optimal penetration depth will vary depending on the thickness of the subject's skin. In most cases, skin is penetrated to a depth of about 0.5-2 mm ... In some embodiments, the formulations are delivered at a targeted depth just under the stratum corneum and encompassing the epidermis and upper dermis, e.g., about 0.025 mm to about 2.5 mm. In other words, Pettis firmly discloses that the formulation/bioactive agents are administered and delivered within the epidermal compartment.
2) Applicant argues that Pettis teaches in para [0076] that the outlet of the needle or cannula is preferably inserted to a depth of 0.3 mm (300 µm) to 1.5 mm. Applicant further states that Pettis does not administered to a plurality of independent depths within the epidermis, as required in claims 1 & 18.
In response, as discussed in claim 1 above, Pettis discloses a method of administering the bioactive agent via microneedle array device (e.g., each of multiple microneedles in the microneedle array represents for a plurality of independent insertions or independent depths). Pettis further discloses that a microneedle (or micro-cannula) with a limited depth of penetration from 10 µm to 2mm, see paras [0077]; the skin is penetrated to a depth of about 0.5-2mm (500 µm-2mm). As mentioned above, the actual optimal penetration depth will vary depending on the thickness of the subject's skin. Therefore, the microneedle is being inserted and contacted one or more layers of epidermis and the bioactive agents diffuses or moves within the epidermis compartment (as supported in para [0082], the formulations are delivered at a targeted depth just under the stratum corneum and encompassing the epidermis and upper dermis, e.g., about 0.025 mm to about 2.5 mm).
3) Applicant argues that nothing in Pettis discloses the limitation “following administration, one or more bioactive agents moves or diffuse deeper through the basal layer of the epidermis and into a portion of the underlying viable dermis to achieve an uptake of a portion of the one or more bioactive agents by one or more susceptible blood capillary plexus or lymphatic capillary plexus.
In response, the limitation above is a functional limitation or inherent result of administering 2 to 50,000 sub-doses of the bioactive agent(s) at an insertion depth ranging from 0.025 to 2.5 mm (25 to 2500 µm, see para [0082]), which falls within the required range of 1 to about 500 µm) beyond the most superficial surface layer of the subject's epidermis. It is noted that when the bioactive agent is delivered at a target depth, it does not stay within the target area; instead, it diffuses deeper through the basal layer of the epidermis and into at least a portion of the underlying viable dermis.
Nevertheless, Pettis discloses the administration of 2 to 50,000 sub-doses of bioactive agent(s) with an insertion depth ranging from 0.025 to 2.5 mm (25 to 2500 µm), which falls within the required range of 1 to 500 µm, beyond the superficial surface layer of the epidermis.
Therefore, Pettis clearly discloses the required limitations—specifically, that following administration, the bioactive agent(s) move or diffuse deeper through the basal layer of the epidermis and into at least a portion of the underlying viable dermis (para [0021]), achieving uptake by the lymphatic capillary plexus.
4) Applicant argues that nothing in Pettis discloses that dermal interstitial fluid pressure greater than 1-15 mmHg.
In response, although Pettis does not mention the fluid pressure at a site of administration of about 1-15 mmHg; however, it would have been obvious to a person having ordinary skill in the art at the time the invention was made to determine the aforementioned values, since it has been held that discovering optimum values (e.g., 1 mmHg to about 15 mmHg) of a result-effective variable involves only routine skill in the art. For example, dermal interstitial fluid pressure depends on the specific skin characteristics of each patient (such as children, adults, males, females, or the elderly) and the amount of pressure or force applied during injection into the target epidermis. Additionally, when delivering drugs via a microneedle array (MNA) device, managing fluid pressure at the target area (the dermis or epidermis) provides critical therapeutic benefits; maintaining low pressure reduces pain, tissue damage, and uneven absorption. MNAs distribute the total fluid volume across dozens or hundreds of microchannels simultaneously. By spreading the volumetric flow rate across an array, the fluid velocity and localized pressure at each individual microneedle tip are substantially reduced, thereby preventing the sudden, intense tissue compaction responsible for injection pain.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QUYNH-NHU HOANG VU whose telephone number is (571)272-3228. The examiner can normally be reached M-F 7:30 am-4:00 pm.
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/QUYNH-NHU H. VU/ Primary Examiner, Art Unit 3783
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