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 .
Response to Amendment
The amendment filed on 08/27/26 has been entered in the case. Claims 1-10, 12-19, 21 are pending for examination and claims 11 & 20 are cancelled.
112 6th Acknowledgement
With regard to Applicant’s “means for penetrating at least a most superficial layer of the epidermis” of claim 5, 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 penetrating at least a most superficial layer of the epidermis” as a needle. Accordingly, the examiner is interpreting the “means for penetrating at least a most superficial layer of the epidermis” 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 1-7, 9-10, 12-19 are rejected under 35 U.S.C. 103 as being unpatentable over Allen et al. (US 6,334,856).
Regarding claim 1, Allen discloses a method of treating a subject with a disease comprising one or more sites of lymphadenitis (col. 3, line 66) by administering one or more bioactive agents to the one or more sites of lymphadenitis comprising:
Note: The recitation that “a disease comprising one or more sites of lymphadenitis by administering one or more bioactive agents to the one or more sites of lymphadenitis” has not been given patentable weight because it has been held that a preamble is denied the effect of a limitation where the claim is drawn to a structure and the portion of the claim following the preamble is a self-contained description of the structure not depending for completeness upon the introductory clause. Kropa v. Robie, 88 USPQ 478 (CCPA 1951).
Lymphadenitis is a specific pathological condition characterized by inflamed or infected lymph nodes. The current application describes the use of a delivery device—specifically, microneedles containing one or more bioactive agents—that targets lymphatic tissue to treat or manage lymphadenitis.
Similarly, Allen explicitly teaches methods and devices for transporting material into or across biological barriers including lymphatic vessels; or cell membranes. The treatment includes bacteria, yeast, fungi... col. 3, line 62-col. 4, line 4. Because lymphadenitis is pathologically defined as the inflammation or infection of the lymph nodes and vessels, the aforementioned limitation—treating a subject with a disease comprising one or more sites of lymphadenitis by administering a bioactive agent to those sites—is recited in the preamble and merely constitutes a statement of intended use or purpose. Allen discloses a method of delivering a therapeutic agent directly into the local lymphatic drainage pathway. Therefore, a person of ordinary skill in the art would recognize that the method and device disclosed in Allen can be used to treat any underlying disease occurring at those specific lymphatic sites, thereby satisfying the intended purpose of treating a disease at a site of lymphadenitis.
(a) applying one or more delivery devices having between 2 and 50,000 delivery structures (e.g. multiple microneedle arrays, Fig. 1A. Therefore, the delivery device or the needle having more than 2 or between 2 to 50,000 delivery structures to one or more sites of a skin of a subject having lymphatic vasculature, (lymphatic vessels, col. 3, line 66), wherein the delivery device contacts one or more layers of epidermis with one or more reversible permeability enhancers comprising a chemical, physical or electrical permeability enhancer, col 7, lines 31-36, that will bring a result of inducing a reversible increase in the permeability of one or more barrier cells of the epidermis to at least one or more bioactive agents;
(b) administering a total liquid dosage (total amount of injection) in between 2 and 50,000 sub-doses of the one or more bioactive agents at a controlled administration flow rate through the delivery device, col. 16, lines 46-66.
Note: each of the microneedle arrays holds at least one small sub-doses (compare with a total liquid dosage = total amount of each sub-doses contained in the microneedle arrays) for inserting into target sites.
wherein each sub-dose (holding by each of the microneedles) of the one or more bioactive agents is independently administered (each of the microneedle arrays holds independently at least one sub-dose of the bioactive agent), in an administering step, to a plurality of independent depths ranging from about less than 100 µm, more preferably about 30 µm, (col. 9, lines 2-4, which is in a required range of 1 to about 500 µm) beyond a most superficial surface layer of the epidermis of the subject, but still within the epidermis of the subject, prior to any subsequent diffusion or movement of the one or more bioactive agents within the epidermis, see Fig. 1A;
Regarding the limitation wherein, following administration, one or more bioactive agents 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 lymphatic capillary plexus to achieve a greater delivery of the one or more bioactive agents to the lymphatic vasculature compared to intravenous, intradermal, or subcutaneous delivery of the identical one or more bioactive agents, 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 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, Allen discloses a method of providing 2 to 50,000 sub-doses of the bioactive agents with the insertion into the epidermis (a plurality of independent depths ranging from 1 to less 100 µm). Therefore, following the administering step, the result of the one or more bioactive agents in Allen 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 lymphatic capillary plexus to achieve a greater delivery of the one or more bioactive agents to the lymphatic vasculature (e.g. the transport of material, i.e. bioactive agents into or across the lymphatic vessels, col. 3, lines 60-66) compared to intravenous, intradermal, or subcutaneous delivery of the identical one or more bioactive agents
Regarding the limitation “wherein after administration and uptake, the one or more bioactive agents circulates through the lymphatic vasculature to one or more secondary lymphatic tissues comprising one or more lymph nodes, thereby -65-38108-491administering the one or more bioactive agents to the one or more sites of lymphadenitis”, 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) with insertion depth from 1-500 µm, i.e. within the epidermis layer. In this case, Allen discloses a same concept of using microneedle arrays (having between 2 to 50,000 delivery/needle structures) for delivering one or more bioactive agent in combine with one or more permeability enhancers into the epidermis tissue and therefore, the bioactive agents is moving and diffusing deeper through the epidermis through a basal layer of the epidermis and into at least a portion of underlying viable dermis and through to lymphatic vasculature (i.e. the bioactive agent into or across the lymphatic vessels, col. 3, lines 60-66) to one more secondary lymphatic tissue comprising one or more lymph nodes, thereby administering the one or more bioactive agents to the one or more sites of lymphadenitis.
In addition, Applicant admits in paras [0101-1003], or it is well-known (or inherently) that lymphatic vessels are vessels that form pathways for discharging tissue fluid separate from circulation system. Therefore, when the bioactive agent moves into or through the lymphatic vascular to one or more secondary lymphatic tissue in circulation flowing.
Regarding claim 2, Allen shows in Fig. 1A that the length of each microneedle 12 is about same length; wherein the length of each needle is less than 100 µm. Therefore, an average of the plurality of independent depths exhibits a combined average sub-dose delivery depth within the epidermis, e.g., a plurality of independent depths ranging from 1 to less 100 µm, col. 9, lines 2-4 and also see Fig. 1A, which is beyond a most superficial surface layer of the epidermis.
Regarding claim 3, similar to the analysis as mentioned in the claim 2 above. Allen also discloses that wherein the plurality of independent depths has a combined average depth of administration within the epidermis, wherein each independently administered sub-dose is at a depth within the epidermis that is deeper, shallower, or the same.
Regarding claim 4, as best as understood, Allen also discloses that wherein a frequency of each of the independent sub-dose administration depths within the viable epidermal layer and/or a non-viable epidermal layer exhibits a Gaussian distribution (normal distribution) of depths.
Regarding claim 5, Allen discloses that wherein the delivery device comprises an array (multiple microneedle arrays) 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 (a reservoir for holding the bioactive agent within the upper portion 11, co. 15, lines 64-65; or a channel/lumen/bore formed in a hollow of the microneedle for delivering drugs, or micropump, col. 5, lines 8-26, col. 7, lines 7-15);
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 (micropumps), a fluid delivery rate controller, or any combination thereof, see col. 7,lines 1-21;
wherein the delivery structures comprise a means (i.e. microneedle arrays device or needle) for penetrating at least a most superficial layer of the epidermis, see Fig. 1A; and
wherein the one or more bioactive agents in a liquid carrier vehicle is delivered by the delivery structures to the plurality of depths within the viable epidermis of a subject, thereby administering between 2 and 50,000 sub-doses of the one or more bioactive agents.
Regarding claim 6, Allen discloses that wherein the delivery structures comprise a standard or nonstandard geometric shape, col. 5, lines 27-57.
Regarding claim 7, Allen discloses that wherein the delivery structures comprise needles.
Regarding claim 8, this claim is being rejected using same analysis as noted in the claim 1 above. However, Allen does not disclose the limitation that the flow rate about 0.01-100 µl/hr per each of the delivery structures at a total combined controlled administration flow rate about 0.02-50,000 µl/hr/cm2 based on a total surface area of the one or more delivery devices that is in contact with the skin of the subject.
It would have been obvious to one having ordinary skill in the art at the time of the invention was made to provide a flow rate the flow rate about 0.01-100 µl/hr per each of the delivery structures at a total combined controlled administration flow rate about 0.02-50,000 µl/hr/cm2, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. For example: it depends on type of skin of children, male, female ... it also depends on age, and depends on each treatment of the disease. In addition, the flow rate based on the total surface area that depends on the size of tumors, the treatment of each condition of a patient.
Regarding claim 9, Allen discloses the claimed invention, as discussed in the claim 1 above. Allen further 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 re more bioactive agent within the epidermis at variable volume rates, col. 16, lines 20-col. 17, line 12. However, Allen does not disclose the volume of the delivered bioactive agent of about 0.7 mm3 to about 2,500 mm3. It would have been obvious to one having ordinary skill in the art at the time of the invention was made to obtain the values above, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In addition, it depends on the treatment of each patient such as number of doses, or pressure/force being injected into the target epidermis.
Regarding claim 10, Allen discloses the claimed invention, as discussed in the claim 110. The method according to claim 1. Allen discloses that the one or more bioactive agents is continuously administered to a subject for a time period of about 0.1 hours to about 96 hours (e.g. the device is affixed to the skin or other tissue to deliver drugs continuously... ranging from a few seconds to several hours to days, col 16, lines 60-63.
Regarding claim 12, Allen discloses that the physical permeability enhancer comprises a nanostructured (nanometers, col. 9, lines 41-42), or nanotopography surface (e.g. porous structure, col. 5, lines 7-13, col. 11, lines 15-46.
Regarding claim 13, Allen discloses the claimed invention, as discussed in the claim 1 above except for 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. It would have been obvious to a person having ordinary skill in the art at the time the invention was made to arrive at the values above, as discovering optimal values for a result-effective variable involves only routine skill. For example, the dermal interstitial fluid pressure value depends on the skin characteristics of the patient (e.g., child, adult, male, female, or elderly) as well as the injection pressure or force applied to the target epidermis.
Regarding claim 14, Allen discloses the claimed invention, as discussed in the claim 1 above. Allen discloses that the insertion of the microneedles into skin was capable of dramatically increasing permeability to calcein, more than 1000-fold, col. 20, lines 48-52. Meanwhile, the claimed invention requires that wherein a relative concentration of one or more bioactive agents within the one or more lymphatic tissues is about 1.25 fold to about 50 fold more than intravenous, intradermal, or subcutaneous delivery of the identical one or more bioactive agents.
It would have been obvious to a person having ordinary skill in the art at the time the invention was made to optimize the values recited above. It is well-established that the discovery of an optimum value of a result-effective variable involves only routine skill in the art to improve the delivery method of a biologically active agent through a target area.
Regarding claim 15, as best as understood, Allen discloses the claimed invention, as discussed in the claim 1 above. A person skilled in the art would recognize that wherein a blood serum absorption rate of the one or more bioactive agents is equivalent to intradermal delivery and subcutaneous delivery of the identical one or more bioactive agents.
Regarding claims 16-17, Allen discloses the claimed invention, as discussed in the claim 1 above except for the limitations that wherein a ratio of an initial dose of one or more bioactive agents localized per gram of lymph node tissue to a whole blood tissue is from about 5:1 to about 15:1 after about 36 hours.
It would have been obvious to one having ordinary skill in the art at the time of the invention was made to obtain the values above, since it has been held that discovering these ratio values in claims 16-17 of a result effective variable involves only routine skill in the art. For example: it depends on each treatment of each patient that determined by a physician.
Regarding claim 18, Allen discloses the claimed invention, as discussed in the claim 1 above 18. The method according to claim 1, wherein the bioactive agent is useful for treating, retarding the progression of, delaying the onset of, or reducing the symptoms of an auto immune disease comprising at least one or more areas of lymphadenitis, col. 3, line 60-col. 4, line 4.
Regarding claim 19, Allen discloses a method of treating a subject with a disease comprising one or more sites of lymphadenitis (col. 3, line 66) by administering one or more bioactive agents to the one or more sites of lymphadenitis comprising:
Note: The recitation that “a disease comprising one or more sites of lymphadenitis by administering one or more bioactive agents to the one or more sites of lymphadenitis” has not been given patentable weight because it has been held that a preamble is denied the effect of a limitation where the claim is drawn to a structure and the portion of the claim following the preamble is a self-contained description of the structure not depending for completeness upon the introductory clause. Kropa v. Robie, 88 USPQ 478 (CCPA 1951).
Lymphadenitis is a specific pathological condition characterized by inflamed or infected lymph nodes. The current application describes the use of a delivery device—specifically, microneedles containing one or more bioactive agents—that targets lymphatic tissue to treat or manage lymphadenitis.
Similarly, Allen explicitly teaches methods and devices for transporting material into or across biological barriers including lymphatic vessels; or cell membranes. The treatment includes bacteria, yeast, fungi... col. 3, line 62-col. 4, line 4. Because lymphadenitis is pathologically defined as the inflammation or infection of the lymph nodes and vessels, the aforementioned limitation—treating a subject with a disease comprising one or more sites of lymphadenitis by administering a bioactive agent to those sites—is recited in the preamble and merely constitutes a statement of intended use or purpose. Allen discloses a method of delivering a therapeutic agent directly into the local lymphatic drainage pathway. Therefore, a person of ordinary skill in the art would recognize that the method and device disclosed in Allen can be used to treat any underlying disease occurring at those specific lymphatic sites, thereby satisfying the intended purpose of treating a disease at a site of lymphadenitis.
(a) applying one or more delivery devices having between 2 and 50,000 delivery structures (e.g. multiple microneedle arrays, Fig. 1A. Therefore, the delivery device or the needle having more than 2 or between 2 to 50,000 delivery structures to one or more sites of a skin of a subject having lymphatic vasculature, (lymphatic vessels, col. 3, line 66), wherein the delivery device contacts one or more layers of epidermis with one or more reversible permeability enhancers comprising a chemical, physical or electrical permeability enhancer, col 7, lines 31-36, that will bring a result of inducing a reversible increase in the permeability of one or more barrier cells of the epidermis to at least one or more bioactive agents;
(b) administering a total liquid dosage (total amount of injection) in between 2 and 50,000 sub-doses of the one or more bioactive agents at a controlled administration flow rate through the delivery device, col. 16, lines 46-66.
Note: each of the microneedle arrays holds at least one small sub-doses (compare with a total liquid dosage = total amount of each sub-doses contained in the microneedle arrays) for inserting into target sites.
wherein each sub-dose (holding by each of the microneedles) of the one or more bioactive agents is independently administered (each of the microneedle arrays holds independently at least one sub-dose of the bioactive agent), in an administering step, to a plurality of independent depths ranging from about less than 100 µm, more preferably about 30 µm, (col. 9, lines 2-4, which is in a required range of 1 to about 500 µm) beyond a most superficial surface layer of the epidermis of the subject, but still within the epidermis of the subject, prior to any subsequent diffusion or movement of the one or more bioactive agents within the epidermis, see Fig. 1A. The Fig. 1A shows that the length of the microneedles 12 are about same length; therefore, an average of the plurality of independent depths exhibits a combine average sub-dose delivery depth (in each of the microneedles 12) within the epidermis of about less than 100 µm, which is in the required range of about 70 µm to 175 µm beyond a most superficial surface layer of the epidermis 16, see Fig. 1A.
Regarding the limitation wherein, following administration, one or more bioactive agents 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 lymphatic capillary plexus to achieve a greater delivery of the one or more bioactive agents to the lymphatic vasculature compared to intravenous, intradermal, or subcutaneous delivery of the identical one or more bioactive agents, 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 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, Allen discloses a method of providing 2 to 50,000 sub-doses of the bioactive agents with the insertion into the epidermis (a plurality of independent depths ranging from 1 to less 100 µm, more preferably about 30 µm). Therefore, following the administering step, the result of the one or more bioactive agents in Allen 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 lymphatic capillary plexus to achieve a greater delivery of the one or more bioactive agents to the lymphatic vasculature (e.g. the transport of material, i.e. bioactive agents into or across the lymphatic vessels, col. 3, lines 60-66) compared to intravenous, intradermal, or subcutaneous delivery of the identical one or more bioactive agents
Regarding the limitation “wherein after administration and uptake, the one or more bioactive agents circulates through the lymphatic vasculature to one or more secondary lymphatic tissues comprising one or more lymph nodes, thereby -65-38108-491administering the one or more bioactive agents to the one or more sites of lymphadenitis”, 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) with insertion depth from 1-500 µm, i.e. within the epidermis layer. In this case, Allen discloses a same concept of using microneedle arrays (having between 2 to 50,000 delivery/needle structures) for delivering one or more bioactive agent in combine with one or more permeability enhancers into the epidermis tissue and therefore, the bioactive agents is moving and diffusing deeper through the epidermis through a basal layer of the epidermis and into at least a portion of underlying viable dermis and through to lymphatic vasculature (i.e. the bioactive agent into or across the lymphatic vessels, col. 3, lines 60-66) to one more secondary lymphatic tissue comprising one or more lymph nodes, thereby administering the one or more bioactive agents to the one or more sites of lymphadenitis.
In addition, Applicant admits in paras [0101-1003], or it is well-known (or inherently) that lymphatic vessels are vessels that form pathways for discharging tissue fluid separate from circulation system. Therefore, when the bioactive agent moves into or through the lymphatic vascular to one or more secondary lymphatic tissue in circulation flowing.
Regarding the limitation—wherein following administration, the permeability of the one or more barrier cells of the epidermis returns to a normal state prior to contacting the one or more layers of epidermis with the one or more reversible permeability enhancers—is a functional limitation or a result of the bioactive agent being administered beyond a most superficial surface layer of the epidermis. In other words, the bioactive agent penetrates into one or more barrier cells within the epidermis, resulting in those cells returning to their normal state prior to contact with the reversible permeability enhancers.
In this case, the Allen reference discloses delivering a formulation into the skin at a target depth of less than 100 micrometers, which is beyond the most superficial surface of the epidermis but still within the epidermis layer. Because Allen explicitly injects or delivers the drug past the surface layer and directly into the epidermis, it inherently produces the exact same result. By definition, delivering a drug at the depths Pettis describes causes the drug to penetrate the barrier cells of the epidermis, inherently causing them to return to their baseline state prior to contact with the enhancers.
Regarding claim 21, the limitation—wherein following administration, the permeability of the one or more barrier cells of the epidermis returns to a normal state prior to contacting the one or more layers of epidermis with the one or more reversible permeability enhancers—is a functional limitation or a result of the bioactive agent being administered beyond a most superficial surface layer of the epidermis. In other words, the bioactive agent penetrates into one or more barrier cells within the epidermis, resulting in those cells returning to their normal state prior to contact with the reversible permeability enhancers.
In this case, the Allen reference discloses delivering a formulation into the skin at a target depth of less than 100 micrometers, which is beyond the most superficial surface of the epidermis but still within the epidermis layer. Because Allen explicitly injects or delivers the drug past the surface layer and directly into the epidermis, it inherently produces the exact same result. By definition, delivering a drug at the depths Pettis describes causes the drug to penetrate the barrier cells of the epidermis, inherently causing them to return to their baseline state prior to contact with the enhancers.
Claims 1-10, 13-19 & 21 are rejected under 35 U.S.C. 103 as being unpatentable over Pettis et al. (US 2005/0180952).
Regarding claim 1, Pettis discloses a method of treating a subject with a disease comprising one or more sites of lymphadenitis by administering one or more bioactive agents to the one or more sites of lymphadenitis.
Note: The recitation that “a disease comprising one or more sites of lymphadenitis by administering one or more bioactive agents to the one or more sites of lymphadenitis” has not been given patentable weight because it has been held that a preamble is denied the effect of a limitation where the claim is drawn to a structure and the portion of the claim following the preamble is a self-contained description of the structure not depending for completeness upon the introductory clause. Kropa v. Robie, 88 USPQ 478 (CCPA 1951).
Lymphadenitis is a specific pathological condition characterized by inflamed or infected lymph nodes. The current application describes the use of a delivery device—specifically, microneedles containing one or more bioactive agents—that targets lymphatic tissue to treat or manage lymphadenitis.
Similarly, Pettis explicitly teaches methods and devices for administering therapeutic substances—namely, one or more bioactive agents such as anti-infectives, antibiotics, and anti-inflammatory components—via intradermal injection optimized for immediate uptake into the capillary lymphatic network or lymphatic tissue (e.g., lymph nodes) (see paras. [0014–0015] and [0017]). Because lymphadenitis is pathologically defined as the inflammation or infection of the lymph nodes and vessels, the aforementioned limitation—treating a subject with a disease comprising one or more sites of lymphadenitis by administering a bioactive agent to those sites—is recited in the preamble and merely constitutes a statement of intended use or purpose. Pettis discloses a method of delivering a therapeutic agent directly into the local lymphatic drainage pathway. Therefore, a person of ordinary skill in the art would recognize that the method and device disclosed in Pettis can be used to treat any underlying disease occurring at those specific lymphatic sites, thereby satisfying the intended purpose of treating a disease at a site of lymphadenitis.
Pettis discloses the method 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 having lymphatic vasculature, (see abstract, para [0002]), 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 (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 ranging 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, which discloses a preferred range of 1 to about 500 µm) beyond the most superficial surface layer of the epidermis (e.g., just under the stratum corneum), but still within the epidermis of the subject (e.g., 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), prior to any subsequent diffusion or movement of the 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);
Regarding the limitation wherein, following administration, one or more bioactive agents 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 lymphatic capillary plexus to achieve a greater delivery of the one or more bioactive agents to the lymphatic vasculature compared to intravenous, intradermal, or subcutaneous delivery of the identical one or more bioactive agents, 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 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.
In addition, Pettis states in para [0070] that the agent has a higher tissue bioavailability in a particular tissue compared to when it is delivered by another route, such as SC, intramuscular, intravenous, or epidermal delivery. In other words, using microneedles 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.
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 and greater delivery to the lymphatic vasculature compared to intravenous, intradermal (for example: a standard needle or a single-microneedle with syringe ) or subcutaneous delivery.
Note: 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.
Regarding the limitation wherein, after administration and uptake, the one or more bioactive agents circulate through the lymphatic vasculature to one or more secondary lymphatic tissues comprising one or more lymph nodes—thereby administering the one or more bioactive agents to the one or more sites of lymphadenitis—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). Therefore, the bioactive agents circulate—achieving distribution with high bioavailability to the lymphatic tissue local to the administration site, followed by more widespread lymphatic delivery into the general circulation (para. [0015]) and diffuse deeper through the epidermis, past the basal layer, into at least a portion of the underlying viable dermis, and through to one or more secondary lymphatic tissues comprising one or more lymph nodes (para. [0017]), thereby administering the one or more bioactive agents to the one or more sites of lymphadenitis.
Regarding claim 2, Pettis discloses that wherein an average of the plurality of independent depths exhibits a combined average sub-dose delivery depth within the epidermis of about 0.025 to 2.5 mm (250-2500 µm, para [0082], which is within the required ranges of 70-175 µm) beyond a most superficial surface layer of the epidermis.
Regarding claim 3, similar to the analysis as mentioned in claim 2 above. Pettis also discloses that wherein the plurality of independent depths has a combined average depth of administration within the epidermis, wherein each independently administered sub-dose is at a depth within the epidermis that is deeper, shallower, or the same. For example: each patient has different thickness value of the epidermis tissue and depend on a target treatment area in deep or shallow area.
Regarding claim 4, as best as understood, Pettis also discloses that wherein a frequency of each of the independent sub-dose administration depths within the viable epidermal layer and/or a non-viable epidermal layer exhibits a Gaussian distribution (normal distribution) of depths.
Regarding claim 5, Pettis discloses that wherein the delivery device comprises an array (multiple microneedle arrays, para [0080], therefore the microneedle arrays is more than 2), 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 (a reservoir for holding bioactive agent or a holder, paras [0089-0090, 0098]);
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, a pen, an elastomer membrane, or any combination thereof, see paras [0090, 0098])
wherein the delivery structures comprise a means (i.e. microneedle arrays device or needle) for penetrating at least a most superficial layer of the epidermis; and wherein the one or more bioactive agents in a liquid carrier vehicle is delivered by the delivery structures to the plurality of depths within the viable epidermis of a subject, thereby administering between 2 and 50,000 sub-doses of the one or more bioactive agents.
Regarding claim 6, Pettis discloses that wherein the delivery structures comprise a standard or nonstandard geometric shape, para [0080].
Regarding claim 7, Pettis discloses that wherein the delivery structures comprise microneedles or needles.
Regarding claim 8, this claim is being rejected using same analysis as noted in claim 1 above. However, Pettis does not disclose the limitation that the flow rate about 0.01-100 µl/hr per each of the delivery structures at a total combined controlled administration flow rate about 0.02-50,000 µl/hr/cm2 based on a total surface area of the one or more delivery devices that is in contact with the skin of the subject.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) at the time the invention was made to provide a flow rate of about 0.01–100 µl/hr for each of the delivery structures, yielding a total combined controlled administration flow rate of about 0.02–50,000 µl/hr/cm². It has been held that discovering an optimum value of a result-effective variable involves only routine skill in the art. For instance, the optimal flow rate depends on patient-specific factors such as age, biological sex, and skin type, as well as the specific disease being treated. Additionally, the flow rate based on total surface area depends heavily on tumor size and the individual clinical condition of the patient.
Regarding claim 9, Pettis discloses the claimed invention, as discussed in the claim 1 above except for the limitation that 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 except for the value of diffusion or movement of the one or more bioactive agents within the epidermis 0.7 mm3 to about 2,500 mm3.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to obtain the values above, since discovering an optimum value of a result-effective variable typically involves only routine skill. In addition, the exact parameters depend on individual patient treatment, such as the number of doses or the pressure and force applied to the target epidermis.
Regarding claim 10, Pettis discloses the claimed invention, as discussed in claims 1 & 10. It is well known in the medical art that to treat cancer, or depending on the patient's condition, a physician must prescribe a treatment administered continuously over a certain period. Determining a continuous administration period of about 0.1 hours to about 96 hours requires only routine skill in the art. For example, the specification discloses a 5-to-10-second injection, see para [0079], and delivery to lung tissue over 3 hours-7days, see para [0230].
Regarding claim 13, Pettis discloses the claimed invention, as discussed in the claim 1 above except for 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. It would have been obvious to a person having ordinary skill in the art at the time the invention was made to arrive at the values above, as discovering optimal values for a result-effective variable involves only routine skill. For example, the dermal interstitial fluid pressure value depends on the skin characteristics of the patient (e.g., child, adult, male, female, or elderly) as well as the injection pressure or force applied to the target epidermis.
Regarding claim 14, Pettis discloses the claimed invention as discussed with respect to claim 1 above. Pettis further discloses that the relative concentration of one or more bioactive agents within the one or more lymphatic tissues is about ½ fold, or 5–10 fold, compared to the dose of the agent conventionally delivered by other routes of administration, such as subcutaneous, intravenous, or intradermal delivery (see para. [0064]). These values fall within the required range of 1.25 fold to about 50 fold more than intravenous, intradermal, or subcutaneous delivery of the identical bioactive agent(s). Furthermore, it would have been obvious to a person having ordinary skill in the art at the time the invention was made to optimize the values recited above. It is well-established that the discovery of an optimum value of a result-effective variable involves only routine skill in the art to improve the delivery method of a biologically active agent through a target area.
Regarding claim 15, as best as understood, Pettis discloses the claimed invention, as discussed in the claim 1 above. A person skilled in the art would recognize that wherein a blood serum absorption rate of the one or more bioactive agents is equivalent to intradermal delivery and subcutaneous delivery of the identical one or more bioactive agents.
Regarding claims 16-17, Pettis discloses the claimed invention, as discussed in the claim 1 above except for the limitations that wherein a blood serum absorption rate of the one or more bioactive agents is equivalent to intradermal delivery and subcutaneous delivery of the identical one or more bioactive agents; wherein a ratio of an initial dose of one or more bioactive agents localized per gram of lymph node tissue to a whole blood tissue is from about 5:1 to about 15:1 after about 36 hours.
It would have been obvious to one having ordinary skill in the art at the time of the invention was made to obtain the values above, since it has been held that discovering these ratio values in claims 16-17 of a result effective variable involves only routine skill in the art. For example: it depends on each treatment of each patient that determined by a physician.
Regarding claim 18, Pettis discloses the claimed invention, as discussed in the claim 1 above, wherein the bioactive agent is useful for treating, retarding the progression of, delaying the onset of, prophylaxis of, amelioration of, or reducing the symptoms of an auto immune disease comprising at least one or more areas of lymphadenitis, see abstract, paras [0014-0017].
Regarding claim 19, this claim is being rejected using same analysis as noted in the claims 1 & 21.
Pettis discloses a method of treating a subject with a disease comprising one or more sites of lymphadenitis by administering one or more bioactive agents to the one or more sites of lymphadenitis.
Note: The recitation that “a disease comprising one or more sites of lymphadenitis by administering one or more bioactive agents to the one or more sites of lymphadenitis” has not been given patentable weight because it has been held that a preamble is denied the effect of a limitation where the claim is drawn to a structure and the portion of the claim following the preamble is a self-contained description of the structure not depending for completeness upon the introductory clause. Kropa v. Robie, 88 USPQ 478 (CCPA 1951).
Lymphadenitis is a specific pathological condition characterized by inflamed or infected lymph nodes. The current application describes the use of a delivery device—specifically, microneedles containing one or more bioactive agents—that targets lymphatic tissue to treat or manage lymphadenitis.
Similarly, Pettis explicitly teaches methods and devices for administering therapeutic substances—namely, one or more bioactive agents such as anti-infectives, antibiotics, and anti-inflammatory components—via intradermal injection optimized for immediate uptake into the capillary lymphatic network or lymphatic tissue (e.g., lymph nodes) (see paras. [0014–0015] and [0017]). Because lymphadenitis is pathologically defined as the inflammation or infection of the lymph nodes and vessels, the aforementioned limitation—treating a subject with a disease comprising one or more sites of lymphadenitis by administering a bioactive agent to those sites—is recited in the preamble and merely constitutes a statement of intended use or purpose. Pettis discloses a method of delivering a therapeutic agent directly into the local lymphatic drainage pathway. Therefore, a person of ordinary skill in the art would recognize that the method and device disclosed in Pettis can be used to treat any underlying disease occurring at those specific lymphatic sites, thereby satisfying the intended purpose of treating a disease at a site of lymphadenitis.
Pettis discloses the method 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 having lymphatic vasculature, (see abstract, para [0002]), 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 ranging 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, which discloses a preferred range of 1 to about 500 µm) beyond the most superficial surface layer of the epidermis (e.g., just under the stratum corneum), but still within the epidermis of the subject (e.g., 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), prior to any subsequent diffusion or movement of the 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);
wherein an average of the plurality of independent depths exhibits a combined average sub-dose delivery depth with the epidermis of about 70 to 175 µm beyond a most superficial surface layer of the epidermis (e.g., 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 = 25-2500 µm)
Regarding the limitation wherein, following administration, one or more bioactive agents 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 lymphatic capillary plexus to achieve a greater delivery of the one or more bioactive agents to the lymphatic vasculature compared to intravenous, intradermal, or subcutaneous delivery of the identical one or more bioactive agents, 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.
In addition, Pettis states in para [0070] that the agent has a higher tissue bioavailability in a particular tissue compared to when it is delivered by another route, such as SC, intramuscular, intravenous delivery. In other words, using microneedles 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.
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 and greater delivery to the lymphatic vasculature compared to intravenous, intradermal (a standard needle with syringe) or subcutaneous delivery.
Note: 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.
Regarding the limitation wherein, after administration and uptake, the one or more bioactive agents circulate through the lymphatic vasculature to one or more secondary lymphatic tissues comprising one or more lymph nodes—thereby administering the one or more bioactive agents to the one or more sites of lymphadenitis—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) into the epidermal tissue (as discussed above). Therefore, the bioactive agents circulate—achieving distribution with high bioavailability to the lymphatic tissue local to the administration site, followed by more widespread lymphatic delivery into the general circulation (para. [0015]) and diffuse deeper through the epidermis, past the basal layer, into at least a portion of the underlying viable dermis, and through to one or more secondary lymphatic tissues comprising one or more lymph nodes (para. [0017]), thereby administering the one or more bioactive agents to the one or more sites of lymphadenitis.
Regarding the limitation—wherein following administration, the permeability of the one or more barrier cells of the epidermis returns to a normal state prior to contacting the one or more layers of epidermis with the one or more reversible permeability enhancers—is a functional limitation or a result of the bioactive agent being administered beyond a most superficial surface layer of the epidermis. In other words, the bioactive agent penetrates into one or more barrier cells within the epidermis, resulting in those cells returning to their normal state prior to contact with the reversible permeability enhancers.
In this case, the Pettis reference discloses delivering a formulation into the skin at a target depth of 0.025 to 2.5 mm (25 to 2500 micrometers), which is beyond the most superficial surface of the epidermis but still within the epidermis layer. Because Pettis explicitly injects or delivers the drug past the surface layer and directly into the epidermis, it inherently produces the exact same result. By definition, delivering a drug at the depths Pettis describes causes the drug to penetrate the barrier cells of the epidermis, inherently causing them to return to their baseline state prior to contact with the enhancers.
Regarding claim 21, the limitation—wherein following administration, the permeability of the one or more barrier cells of the epidermis returns to a normal state prior to contacting the one or more layers of epidermis with the one or more reversible permeability enhancers—is a functional limitation or a result of the bioactive agent being administered beyond a most superficial surface layer of the epidermis. In other words, the bioactive agent penetrates into one or more barrier cells within the epidermis, resulting in those cells returning to their normal state prior to contact with the reversible permeability enhancers.
In this case, the Pettis reference discloses delivering a formulation into the skin at a target depth of 0.025 to 2.5 mm (25 to 2500 micrometers), which is beyond the most superficial surface of the epidermis but still within the epidermis layer. Because Pettis explicitly injects or delivers the drug past the surface layer and directly into the epidermis, it inherently produces the exact same result. By definition, delivering a drug at the depths Pettis describes causes the drug to penetrate the barrier cells of the epidermis, inherently causing them to return to their baseline state prior to contact with the enhancers.
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 the invention substantially as claimed invention 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.
It would have been obvious at the time the invention was made to a person having ordinary skill in the art to modify the device of Pettis with providing a physical permeability enhancer with a nanostructured or nanotopography surface, as taught by Ross, in order to allow the surface of the microneedle being interacted with the cells of the dermal barrier and improve efficiency of delivery and uptake of the bioactive agents, para [0071] in Ross.
Response to Arguments
Applicant's arguments filed 08/27/26 have been fully considered but they are not persuasive.
Prior art Allen
1) Applicant argues that the word “lymphadenitis” does not appear anywhere in Allen.
In response, the recitation that “a disease comprising one or more sites of lymphadenitis by administering one or more bioactive agents to the one or more sites of lymphadenitis” has not been given patentable weight because it has been held that a preamble is denied the effect of a limitation where the claim is drawn to a structure and the portion of the claim following the preamble is a self-contained description of the structure not depending for completeness upon the introductory clause. Kropa v. Robie, 88 USPQ 478 (CCPA 1951).
Lymphadenitis is a specific pathological condition characterized by inflamed or infected lymph nodes. The current application describes the use of a delivery device—specifically, microneedles containing one or more bioactive agents—that targets lymphatic tissue to treat or manage lymphadenitis.
Similarly, Allen explicitly teaches methods and devices for transporting material into or across biological barriers including lymphatic vessels; or cell membranes. The treatment includes bacteria, yeast, fungi... col. 3, line 62-col. 4, line 4. Because lymphadenitis is pathologically defined as the inflammation or infection of the lymph nodes and vessels, the aforementioned limitation—treating a subject with a disease comprising one or more sites of lymphadenitis by administering a bioactive agent to those sites—is recited in the preamble and merely constitutes a statement of intended use or purpose. Allen discloses a method of delivering a therapeutic agent directly into the local lymphatic drainage pathway. Therefore, a person of ordinary skill in the art would recognize that the method and device disclosed in Allen can be used to treat any underlying disease occurring at those specific lymphatic sites, thereby satisfying the intended purpose of treating a disease at a site of lymphadenitis.
2) Applicant argues that the Office does not provide evidence that administering an agent at Allen’s depth of about 30 micrometers necessarily produces a greater delivery of that agent to the lymphatic vasculature than intravenous, intradermal or subcutaneous delivery of the identical agent.
In response the limitation above is a result of using microneedle with inserting in a target depth about 1-500 micrometer; wherein the target areas that beyond a most superficial surface layer of the epidermis of the subject, but still within the epidermis of the subject. In addition, Applicant states in para [0119] in the current application that: delivery to the epidermis yields greater lymphatic uptake compared to alternative parenteral delivery methods, such as direct intradermal delivery techniques, which may miss the initial lymphatic capillaries directly below the basement membrane of the epidermis, resulting in reduced lymphatic uptake.
Similarly, Allen discloses that the bioactive agent is delivered by microneedle device at target depth just under the stratum corium and encompassing the epidermis and upper dermis, see Fig. 1A , and therefore, will bring the result of achieving a greater delivery of bioactive agent to the lymphatic vasculature compared with to intradermal delivery such as SC delivery, intramuscular delivery, intravenous delivery, and epidermal delivery.
3) Applicant argues that Allend discloses a single insertion depth, not a plurality of independent depths:
In response, Allen shows in Fig. 1A a microneedle array device 1 comprising a plurality of independent microneedles 12, where each microneedle features a plurality of independent depths.
4) Applicant argues that Allen fails to disclose the limitation that: a combined average sub-dose delivery depth with the epidermis of about 70 to 175 micrometers beyond a most superficial surface layer of the epidermis.
In response, Allen shows in Fig. 1A that the length of each microneedle 12 is about same length; wherein the length of each needle is less than 100 µm. Therefore, an average of the plurality of independent depths exhibits a combined average sub-dose delivery depth within the epidermis, e.g., a plurality of independent depths ranging from 1 to less 100 µm, col. 9, lines 2-4 and also see Fig. 1A, which is beyond a most superficial surface layer of the epidermis.
Prior art Pettis
5) Applicant argues on page 15 of the Remarks that: Pettis fails to disclose the limitation, e.g., the administering achieve “a greater delivery of the one or more bioactive agents to the lymphatic vasculature compared to intravenous, intradermal or subcutaneous delivery of the identical one or more bioactive agents.
In response, the applicant’s statement or 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 1 to about 500 µm beyond the most superficial surface layer of the subject's epidermis. 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 and greater delivery to the lymphatic vasculature compared to intravenous or subcutaneous delivery.
6) Applicant further states that Pettis is an intradermal delivery disclosure, as mentioned in the title, abstract, para [0067] and repeated at paragraph [0021], as "administration of a biologically active agent into the dermis in such a manner that the agent readily reaches the richly vascularized papillary dermis and is rapidly absorbed into the blood capillaries and/or lymphatic vessels to become systemically bioavailable."
In response, Pettis discloses multiple methods in different embodiments for delivering bioactive into a target area, through lymphatic vasculature. The Applicant’s statement above is one of the methods in Pettis.
However, Pettis also states that using microneedles (para [0080]) are inserted to targeted depth just under the stratum corneum encompassing the epidermis and upper dermis (0.025 to 2.5 mm). Note: the microneedles serve in limit the depth of penetration, para [0098].
Therefore, a person skilled in the art would recognize that using the microneedles are delivered the bioactive at targeted depth (0.025 to 2.5 mm) within the epidermis compartment will bring the result that more bioactive agents deliver to the lymphatic vasculature compared with other methods of intravenous, intradermal, or subcutaneous delivery are being inserted deeper in the dermal compartment, also see para [0070] in Pettis..
7) Applicant states on page 15 of the Remarks that at paragraph [0071] it sets its route apart from others, referring to bioavailability "as compared to when the agent is delivered by a route other than intradermal delivery such as SC delivery, intramuscular delivery, intravenous delivery, and epidermal delivery." A reference cannot render obvious a claim that requires outperforming that reference's own route of administration, absent a teaching that some variation would do so. The Office identifies no such teaching and Pettis contains none. The advance Pettis claims is that intradermal delivery is better than subcutaneous, intramuscular and intravenous delivery. Pettis nowhere suggests that anything is better than intradermal delivery.
In response, Applicant states in para [0119] in the current application that: delivery to the epidermis yields greater lymphatic uptake compared to alternative parenteral delivery methods, such as direct intradermal delivery techniques, which may miss the initial lymphatic capillaries directly below the basement membrane of the epidermis, resulting in reduced lymphatic uptake.
Similarly, Pettis discloses that the bioactive agent is delivered by microneedle device at target depth just under the stratum corium and encompassing the epidermis and upper dermis, para [0082], will bring the result of achieving a greater delivery of bioactive agent to the lymphatic vasculature compared with SC delivery, intramuscular delivery, intravenous delivery, and intradermal delivery (a standard needle with syringe). 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
Note: 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.
8) Applicant states that claims 1, 8 and 19 now require that the plurality of independent depths lie within the epidermis of the subject. Pettis measures the epidermis at "a total thickness of between 75 and 150" micrometers. Paragraph [0005]. Every depth at which Pettis directs the agent to be deposited lies beneath it. Applicant further states that paragraph [0021] teaches "placement of a biologically active agent predominately at a depth of at least about 0.3 mm, more preferably, at least about 0.4 mm and most preferably at least about 0.5 mm up to a depth of no more than about 2.5 mm." Paragraph [0082] teaches that "[i]n most cases, skin is penetrated to a depth of about 0.5-2 mm," and that "the methods of the invention preferably targets the formulations of the invention to a depth of at least at least 0.5 mm up to a depth of no more than 2.5 mm, more preferably no more than 2.0 mm, and most preferably no more than 1.7 mm." Those figures are 300 to 2,500 micrometers, against an epidermis of 75 to 150 micrometers.
In response, Pettis discloses in para [0082] that: 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..." It is noted that the disclosed range of 0.025–2.5 mm (25–2,500 µm) overlaps with the required range of 75–150 µm, which sits just under the stratum corneum but still within the epidermal compartment.
9) Applicant argues that Pettis does not disclose lymphadenitis.
In response, The recitation that “a disease comprising one or more sites of lymphadenitis by administering one or more bioactive agents to the one or more sites of lymphadenitis” has not been given patentable weight because it has been held that a preamble is denied the effect of a limitation where the claim is drawn to a structure and the portion of the claim following the preamble is a self-contained description of the structure not depending for completeness upon the introductory clause. Kropa v. Robie, 88 USPQ 478 (CCPA 1951).
Lymphadenitis is a specific pathological condition characterized by inflamed or infected lymph nodes. The current application describes the use of a delivery device—specifically, microneedles containing one or more bioactive agents—that targets lymphatic tissue to treat or manage lymphadenitis.
Similarly, Pettis explicitly teaches methods and devices for administering therapeutic substances—namely, one or more bioactive agents such as anti-infectives, antibiotics, and anti-inflammatory components—via intradermal injection optimized for immediate uptake into the capillary lymphatic network or lymphatic tissue (e.g., lymph nodes) (see paras. [0014–0015] and [0017]). Because lymphadenitis is pathologically defined as the inflammation or infection of the lymph nodes and vessels, the aforementioned limitation—treating a subject with a disease comprising one or more sites of lymphadenitis by administering a bioactive agent to those sites—is recited in the preamble and merely constitutes a statement of intended use or purpose. Pettis discloses a method of delivering a therapeutic agent directly into the local lymphatic drainage pathway. Therefore, a person of ordinary skill in the art would recognize that the method and device disclosed in Pettis can be used to treat any underlying disease occurring at those specific lymphatic sites, thereby satisfying the intended purpose of treating a disease at a site of lymphadenitis.
Examiner Notes
Examiner cites particular columns and line numbers in the references as applied to the claims above for the convenience of the applicant. Although the specified citations are representative of the teachings in the art and are applied to the specific limitations within the individual claim, other passages and figures may apply as well. It is respectfully requested that, in preparing responses, the applicant fully consider the references in entirety as potentially teaching all or part of the claimed invention, as well as the context of the passage as taught by the prior art or disclosed by the examiner.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Tsai can be reached at 571-270-5246. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/QUYNH-NHU H. VU/ Primary Examiner, Art Unit 3783
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