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 3/18/2026 has been entered. Claims 36 and 39-65 are pending in the application. Claims 1-35 and 37-38 are cancelled. The amendments to the claims overcome the claim objection previously set forth in the Non-Final Office Action mailed on 12/19/2025.
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 (i.e., changing from AIA to pre-AIA ) 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 36, 39-40, and 42-45 are rejected under 35 U.S.C. 103 as being unpatentable over Dewhirst et al. ("Transport of drugs from blood vessels to tumour tissue") in view of Peyman (US 2016/0022976 A1) and further in view of Paulides et al. (“Recent technological advancements in radio-frequency- and microwave-mediated hyperthermia for enhancing drug delivery”).
Regarding claim 36, Dewhirst discloses a method for treating cancerous or precancerous cells in a patient (see page 746, tumors are targeted), the method comprising:
administering nanoparticles loaded with at least one anti-cancer agent to a vasculature of the patient (see Fig. 4, pages 746-747), the vasculature being adjacent or at a tumor site (see Fig. 4, page 746), the nanoparticles being configured for delivery of the at least one anti-cancer agent across a wall of the vasculature adjacent to the tumor site in response to hyperthermia generated by a release-triggering energy (see Fig. 4, pages 746-747, thermosensitive liposomes (i.e. nanoparticles) are loaded with a drug and delivered intravascularly to a tumor region where heat is applied to cause hyperthermia that releases the drug from the liposome and the released drug diffuses across the vessel wall and into the tumor); and
applying the release-triggering energy to specified regions within or adjacent to the tumor site to cause the at least one anti-cancer agent to be released from the nanoparticles within the vasculature and across the wall of the vasculature toward the cancerous or precancerous cells (see Fig. 4, pages 746-747, thermosensitive liposomes (i.e. nanoparticles) are loaded with a drug and delivered intravascularly to a tumor region where heat is applied to cause hyperthermia that releases the drug from the liposome and the released drug diffuses across the vessel wall and into the tumor),
wherein the release-triggering energy is applied before, during, or after the administering the nanoparticles (see Fig. 4, pages 746-747, thermosensitive liposomes (i.e. nanoparticles) are loaded with a drug and delivered intravascularly to a tumor region where heat is applied to cause hyperthermia that releases the drug from the liposome and the released drug diffuses across the vessel wall and into the tumor).
While Dewhirst teaches that surgery in combination with delivery of anti-cancer agents can influence the effectiveness of chemotherapeutic treatment (see page 738, col. 1; "In order for cancer chemotherapy to have lasting effects, drugs must be applied to a large fraction (close to 100%) of cancerous cells. Many factors influence the effectiveness of chemotherapeutic treatment, including the use of radiation, surgery or other treatments in combination with chemotherapy"), Dewhirst fails to expressly state that the method is for treating residual cancerous or precancerous cells following tumor surgery in the patient, the nanoparticles being delivered to vasculature that is adjacent or at a surgical cavity and the release-triggering energy is applied to specified regions within or adjacent to the surgical cavity to cause the at least one anti-cancer agent to be released toward the residual cancerous or precancerous cells. Dewhirst further fails to expressly state that the applying the release-triggering energy causes tissue up to a penetration depth in a range from 0.5 cm to 3 cm from a surface of the surgical cavity to be exposed to the hyperthermia.
Peyman teaches a method for treating residual cancerous or precancerous cells following tumor surgery in a patient (see par. [0024]-[0025] and [0177]-[0178]), the nanoparticles being delivered to vasculature that is adjacent or at a surgical cavity and the release-triggering energy is applied to specified regions within or adjacent to the surgical cavity to cause the at least one anti-cancer agent to be released toward the residual cancerous or precancerous cells (see par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Dewhirst to be a method for treating residual cancerous or precancerous cells following tumor surgery in the patient, the nanoparticles being delivered to vasculature that is adjacent or at a surgical cavity and the release-triggering energy is applied to specified regions within or adjacent to the surgical cavity to cause the at least one anti-cancer agent to be released toward the residual cancerous or precancerous cells, as taught by Peyman, because surgery in combination with chemotherapy can influence the effectiveness and long-term effects of the chemotherapy (see Dewhirst page 738, col. 1) and such a combination can include surgical excision of the tumor prior to performing the nano- particle delivery and application of the release-triggering energy near the surgical site (see Peyman par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]).
However, modified Dewhirst still fails to expressly state that the applying the release-triggering energy causes tissue up to a penetration depth in a range from 0.5 cm to 3 cm from a surface of the surgical cavity to be exposed to the hyperthermia.
Paulides teaches a method for treating cancerous or precancerous cells in a patient (see abstract, “Hyperthermia therapy is a potent enhancer of chemotherapy and radiotherapy…These new technologies hold great promise not only for (image-guided perfusion modulation and sensitization for cytotoxic drugs, but also for local delivery of various compounds using thermosensitive liposomes”) comprising applying the release-triggering energy to cause tissue up to a penetration depth of 3 cm from a surface of the surgical cavity to be exposed to the hyperthermia to cause the at least one anti-cancer agent to be released (see page 5, 2.3.1 Superficial hyperthermia, “the typical thermal penetration depth is 3 cm” [for microwave energy]; see page 11, 3.8 Other cancers, “Two pilot studies explored the use of thermally enhanced drug delivery…Heating was achieved with BSD-500 equipment that uses multiple microwave applicators that heat up to 3 cm deep”).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include a penetration depth of the hyperthermia of up to 3 cm, as taught by Paulides, because Dewhirst teaches that microwave energy can be the release-triggering energy to cause the hyperthermia to release the anti-cancer drug (see Dewhirst page 746, “Heating is typically achieved by use of…microwave…applicators”) and Paulides teaches that a penetration depth of up to 3 cm is typical and effective for microwave applicators for enhancing the delivery of drugs from thermosensitive liposomes (Paulides; see abstract, “Hyperthermia therapy is a potent enhancer of chemotherapy and radiotherapy…These new technologies hold great promise not only for (image-guided perfusion modulation and sensitization for cytotoxic drugs, but also for local delivery of various compounds using thermosensitive liposomes”; see page 5, 2.3.1 Superficial hyperthermia, “the typical thermal penetration depth is 3 cm” [for microwave energy]; see page 11, 3.8 Other cancers, “Two pilot studies explored the use of thermally enhanced drug delivery…Heating was achieved with BSD-500 equipment that uses multiple microwave applicators that heat up to 3 cm deep”).
Regarding claim 39, modified Dewhirst teaches the method of claim 36 substantially as claimed. Dewhirst further teaches wherein the hyperthermia is in a range from 40° C to 50° C (see Fig. 4, page 746).
Regarding claim 40, modified Dewhirst teaches the method of claim 36 substantially as claimed. Dewhirst further teaches wherein the nanoparticles comprise thermosensitive liposomes (see Fig. 4, pages 746-747).
Regarding claim 42, modified Dewhirst teaches the method of claim 36 substantially as claimed.
However, modified Dewhirst fails to expressly state wherein the at least one anti-cancer agent has an extraction ratio of more than 0.3 (30%).
Dewhirst teaches that the at least one anti-cancer agent is delivered and released intravascularly (see Dewhirst pages 746-747). Thus, the extraction ratio of the at least one anti-cancer agent is a result effective variable in that adjusting the extraction ratio affects the ability of the method to treat tumors and its ability to be cleared without accumulating in the bloodstream which could result in toxicity. Further, it appears that one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of modified Dewhirst to include an extraction ratio within the claimed range as it involves adjusting a parameter which is capable of adjustment. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include wherein the at least one anti-cancer agent has an extraction ratio of more than 0.3 (30%) as a matter of routine optimization since it has been held that "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Further, Applicant appears to place no criticality on the range claimed, stating that an extraction ratio within the claimed range is preferable but that the specific range is not a critical requirement of the invention (see Specification page 6 lines 216-231, page 10 lines 393- 402).
Regarding claim 43, modified Dewhirst teaches the method of claim 36 substantially as claimed. Dewhirst further teaches wherein the release-triggering energy has one or both of a predetermined duration or a predetermined magnitude (see Fig. 4, page 746, at least a predetermined duration is discussed).
Regarding claim 44, modified Dewhirst teaches the method of claim 36 substantially as claimed. Dewhirst further teaches wherein the at least one anti-cancer agent is fluorescent or tagged with a fluorescent marker, the method further comprising fluorescence imaging to visualize a location and a quantity of the at least one anti- cancer agent one or both of during or after the applying the release-triggering energy (see Fig. 4, pages 746-747, the liposomes can also include an MR contrast agent or radionuclide for direct visualization of drug delivery in near real time).
Regarding claim 45, modified Dewhirst teaches the method of claim 36 substantially as claimed. Dewhirst further teaches exposing a drug delivery region to a predetermined hyperthermic target temperature in a range from 40 to 50 °C (see Fig. 4, page 746).
However, modified Dewhirst fails to expressly state selecting the drug delivery region including at least a part of the surgical cavity based on an image acquired of the surgical cavity and surrounding tissue.
Peyman teaches a method for treating residual cancerous or precancerous cells following tumor surgery in a patient (see par. [0024]-[0025] and [0177]-[0178]), comprising selecting the drug delivery region including at least a part of the surgical cavity based on an image acquired of the surgical cavity and surrounding tissue (see par. [0136] and [0215]-[0216]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include selecting the drug delivery region including at least a part of the surgical cavity based on an image acquired of the surgical cavity and surrounding tissue, as taught by Peyman, in order to allow for enhanced imaging of the tumor while simultaneously providing the drug delivery therapy (see Peyman par. [0136]).
Claims 46-49, 51-53, and 55-64 are rejected under 35 U.S.C. 103 as being unpatentable over Dewhirst et al. ("Transport of drugs from blood vessels to tumour tissue") in view of Peyman (US 2016/0022976 A1) and further in view of Li et al. (“Recent advances in the development of near-infrared organic photothermal agents”).
Regarding claim 46, Dewhirst discloses a method (see Fig. 4, pages 746-747) comprising:
introducing thermosensitive liposomes encapsulating doxorubicin into a bloodstream for delivery inside tissue capillaries, wherein the thermosensitive liposomes are configured for triggered intravascular release in response to hyperthermia at temperatures above 40°C (see Fig. 4, pages 746-747, thermosensitive liposomes are loaded with doxorubicin and delivered intravascularly to tumor microvasculature where heat is applied to cause hyperthermia above 40°C that releases the doxorubicin from the liposome and the released doxorubicin diffuses across the microvasculature wall and into the tumor microvasculature); and
targeting radiation onto a surface near a tumor site to cause at least some of the radiation to penetrate below the surface, wherein the radiation is configured to release the doxorubicin from the thermosensitive liposomes as released doxorubicin inside the tissue capillaries and across a wall of the tissue capillaries, and wherein the released doxorubicin is configured for killing cancer cells in tissue in a vicinity of the surface (see Fig. 4, pages 746-747, thermosensitive liposomes are loaded with doxorubicin and delivered intravascularly to tumor microvasculature where heat is applied to cause hyperthermia above 40°C that releases the doxorubicin from the liposome and the released doxorubicin diffuses across the microvasculature wall and into the tumor microvasculature);
monitoring delivery of the released doxorubicin during radiation exposure of the surface by fluorescence imaging (see Fig. 4, pages 746-747, the liposomes can also include an MR contrast agent or radionuclide for direct visualization of drug delivery in near real time).
While Dewhirst teaches that surgery in combination with delivery of anti-cancer agents can influence the effectiveness of chemotherapeutic treatment (see page 738, col. 1; "In order for cancer chemotherapy to have lasting effects, drugs must be applied to a large fraction (close to 100%) of cancerous cells. Many factors influence the effectiveness of chemotherapeutic treatment, including the use of radiation, surgery or other treatments in combination with chemotherapy"), Dewhirst fails to expressly state that the radiation is targeted onto a surgical cavity surface and the released doxorubicin is configured for killing residual cancer cells remnant in tissue in a vicinity of the surgical cavity surface. Dewhirst also fails to state that the radiation is near-infrared radiation; and monitoring tissue temperature and adjusting near-infrared radiation intensity based on the monitored tissue temperature. Dewhirst further fails to expressly state targeting the near-infrared radiation up to a penetration depth in a range from 0.5 cm to 3 cm from a surface of the surgical cavity to be exposed to the hyperthermia.
Peyman teaches a method (see par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]), comprising targeting near-infrared radiation onto a surgical cavity surface to cause at least some of the near-infrared radiation to penetrate below the surgical cavity surface (see par. [0024]-[0025], [0125]-[0127], [0177]-[0178], [0276]), wherein the released doxorubicin is configured for killing residual cancerous cells remnant in tissue in a vicinity of the surgical cavity surface (see par. [0024]-[0025], [0039], and [0125]- [0127]); and monitoring tissue temperature and adjusting near-infrared radiation intensity based on the monitored tissue temperature (see par. [0084, [0200], and [0276]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Dewhirst to comprise targeting near-infrared radiation onto a surgical cavity surface to cause at least some of the near-infrared radiation to penetrate below the surgical cavity surface, wherein the released doxorubicin is configured for killing residual cancerous cells remnant in tissue in a vicinity of the surgical cavity surface; and monitoring tissue temperature and adjusting near-infrared radiation intensity based on the monitored tissue temperature, as taught by Peyman, because surgery in combination with chemotherapy can influence the effectiveness and long-term effects of the chemotherapy (see Dewhirst page 738, col. 1) and such a combination can include surgical excision of the tumor prior to performing the nano-particle delivery and application of the release-triggering energy near the surgical site (see Peyman par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]); near-infrared radiation is another form of energy suitable for inducing hyperthermia to release doxorubicin from thermosensitive liposomes (see Peyman par. [0039], [0125]-[0127], and [0276]); and monitoring temperature and adjusting the radiation intensity can minimize and prevent pain and overheating (see Peyman par. [0084]).
However, modified Dewhirst still fails to expressly state targeting the near-infrared radiation up to a penetration depth in a range from 0.5 cm to 3 cm from a surface of the surgical cavity to be exposed to the hyperthermia.
Li teaches a method for treating cancerous or precancerous cells in a patient (see abstract) comprising targeting the near-infrared radiation up to a penetration depth in a range from less than 1 cm or 3 cm (see Introduction, “The tissue penetration depth of effective PTTAs in the first near-infrared (NIR-I, 650–950 nm) window is often less than 1 cm, while the second NIR (NIR-II, 1000–1700 nm) laser can penetrate a depth of 3–5 cm [12]”).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include a penetration depth of less than 1 cm or 3 cm, which falls within the claimed range, as taught by Li, because Peyman teaches that near-infrared energy can be the release-triggering energy to cause the hyperthermia to release the anti-cancer drug (see Peyman par. [0024]-[0025], [0125]-[0127], [0177]-[0178], [0276]; see previous modifications in view of Peyman above) and Li teaches that a penetration depth of less than 1 cm or 3 cm is effective for NIR applicators for cancer treatment depending on the type of NIR used (Li; see Introduction, “The tissue penetration depth of effective PTTAs in the first near-infrared (NIR-I, 650–950 nm) window is often less than 1 cm, while the second NIR (NIR-II, 1000–1700 nm) laser can penetrate a depth of 3–5 cm [12]”).
Regarding claim 47, modified Dewhirst teaches the method of claim 46 substantially as claimed. Modified Dewhirst further teaches wherein tissue up to a depth in a range from 0.5 to 2 cm from the surgical cavity surface is heated by the near infrared radiation to temperatures in a range from 40 to 45 °C (see Dewhirst page 746, see previous modifications in view of Peyman and Li in rejection of claim 46 above; see Li Introduction, “The tissue penetration depth of effective PTTAs in the first near-infrared (NIR-I, 650–950 nm) window is often less than 1 cm, while the second NIR (NIR-II, 1000–1700 nm) laser can penetrate a depth of 3–5 cm [12]”).
However, modified Dewhirst fails to expressly state wherein tissue is heated by the near-infrared radiation for a duration in a range from 10 to 60 minutes.
Peyman teaches a method (see par. [0125]-[0127]) wherein tissue is heated by the near-infrared radiation (see par. [0125]-[0127] and [0276]) for a duration in a range from 10 to 60 minutes (see par. [0201]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include wherein tissue is heated by the near-infrared radiation for a duration in a range from 10 to 60 minutes, as taught by Peyman, because these specifics are suitable for killing cancer cells with the method (see Peyman par. [0024]-[0025], [0125]-[0127], [0150], [0177]-[0178], [0201], [0276], and [0279]-[0280]).
Regarding claim 48, modified Dewhirst teaches the method of claim 46 substantially as claimed. Dewhirst further teaches wherein the cancer cells are associated with sarcoma or squamous cell carcinoma (see page 746, sarcomas and squamous cell carcinomas are both taught as target tumors applicable to the method).
However, modified Dewhirst fails to expressly state wherein the residual cancer cells are associated with soft tissue sarcoma or oral cavity squamous cell carcinoma.
Peyman teaches a method (see par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]) wherein the residual cancer cells (see par. [0024]-[0025] and [0177]-[0178]) are associated with soft tissue tumors or oral cavity tumors (see par. [0151] and [0244]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst such that the residual cancer cells are associated with soft tissue sarcoma or oral cavity squamous cell carcinoma, as suggested by Peyman, in order to treat these types of cancers in these locations (see Peyman par. [0151] and [0244]).
Regarding claim 49 modified Dewhirst teaches the method of claim 46 substantially as claimed. Modified Dewhirst further teaches selecting a tissue region comprising at least a part of the surgical cavity surface before the targeting the near-infrared radiation (see Dewhirst page 746, the hyperthermia is applied locally at a specific location; see previous modifications in rejection of claim 46 above),
wherein the targeting the near-infrared radiation comprises exposing the selected tissue region to the near-infrared radiation to heat the selected tissue region and induce release of the doxorubicin from the thermosensitive liposomes (see Dewhirst pages 746-747, the hyperthermia is applied locally to release the doxorubicin where the hyperthermia is applied; see previous modifications in rejection of claim 46 above).
Regarding claim 51, modified Dewhirst teaches the method of claim 46 substantially as claimed. Modified Dewhirst further teaches wherein the near-infrared radiation is targeted before, during, or after the introducing the thermosensitive liposomes into the bloodstream (see Dewhirst Fig. 4, Dewhirst pages 746-747, thermosensitive liposomes are delivered intravascularly to a tumor region where heat is applied to cause hyperthermia; see previous modifications in rejection of claim 46 above).
Regarding claim 52, Dewhirst discloses a method (see Fig. 4, pages 746-747) comprising:
administering thermally triggered nanoparticles configured for intravascular release, loaded with at least one anti-cancer agent, into a bloodstream in a vasculature (see Fig. 4, pages 746-747, thermosensitive liposomes (i.e. nanoparticles) are loaded with a drug and delivered intravascularly to a tumor region where heat is applied to cause hyperthermia that releases the drug from the liposome and the released drug diffuses across the vessel wall and into the tumor); and
applying energy to a tissue surrounding a tumor site defining a surface, wherein the energy is configured to release the at least one anti-cancer agent from the thermally triggered nanoparticles in the bloodstream and across a wall of the vasculature to the tissue surrounding the tumor site (see Fig. 4, pages 746-747, thermosensitive liposomes (i.e. nanoparticles) are loaded with a drug and delivered intravascularly to a tumor region where heat is applied to cause hyperthermia that releases the drug from the liposome and the released drug diffuses across the vessel wall and into the tumor).
While Dewhirst teaches that surgery in combination with delivery of anti-cancer agents can influence the effectiveness of chemotherapeutic treatment (see page 738, col. 1; "In order for cancer chemotherapy to have lasting effects, drugs must be applied to a large fraction (close to 100%) of cancerous cells. Many factors influence the effectiveness of chemotherapeutic treatment, including the use of radiation, surgery or other treatments in combination with chemotherapy"), Dewhirst fails to expressly state that the energy is applied to the tissue surrounding a surgically extracted tumor site defining a surgical cavity surface such that the at least one anti-cancer agent is released to the tissue surrounding the surgically extracted tumor site; and that the energy is near-infrared energy. Dewhirst further fails to expressly state applying the near-infrared radiation up to a penetration depth in a range from 0.5 cm to 3 cm from the surgical cavity surface.
Peyman teaches a method (see par. [0024]-[0025], [0125]-[0127], and [0177]- [0178]) wherein the energy is applied to the tissue surrounding a surgically extracted tumor site defining a surgical cavity surface such that the at least one anti-cancer agent is released to the tissue surrounding the surgically extracted tumor site (see par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]); and wherein the energy is near-infrared energy (see par. [0125]-[0127] and [0276]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Dewhirst such that near-infrared energy is applied to the tissue surrounding a surgically extracted tumor site defining a surgical cavity surface such that the at least one anti-cancer agent is released to the tissue surrounding the surgically extracted tumor site, as taught by Peyman, because surgery in combination with chemotherapy can influence the effectiveness and long-term effects of the chemotherapy (see Dewhirst page 738, col. 1) and such a combination can include surgical excision of the tumor prior to performing the nano-particle delivery and application of the release-triggering energy near the surgical site (see Peyman par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]); and near-infrared radiation is another form of energy suitable for inducing hyperthermia to release anti-cancer drugs from thermally triggered nanoparticles (see Peyman par. [0039], [0125]-[0127], and [0276]).
However, modified Dewhirst still fails to expressly state applying the near-infrared radiation up to a penetration depth in a range from 0.5 cm to 3 cm from the surgical cavity surface.
Li teaches a method for treating cancerous or precancerous cells in a patient (see abstract) comprising applying the near-infrared radiation up to a penetration depth in a range from less than 1 cm or 3 cm (see Introduction, “The tissue penetration depth of effective PTTAs in the first near-infrared (NIR-I, 650–950 nm) window is often less than 1 cm, while the second NIR (NIR-II, 1000–1700 nm) laser can penetrate a depth of 3–5 cm [12]”).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include a penetration depth of less than 1 cm or 3 cm, which falls within the claimed range, as taught by Li, because Peyman teaches that near-infrared energy can be the release-triggering energy to cause the hyperthermia to release the anti-cancer drug (see Peyman par. [0024]-[0025], [0125]-[0127], [0177]-[0178], [0276]; see previous modifications in view of Peyman above) and Li teaches that a penetration depth of less than 1 cm or 3 cm is effective for NIR applicators for cancer treatment depending on the type of NIR used (Li; see Introduction, “The tissue penetration depth of effective PTTAs in the first near-infrared (NIR-I, 650–950 nm) window is often less than 1 cm, while the second NIR (NIR-II, 1000–1700 nm) laser can penetrate a depth of 3–5 cm [12]”).
Regarding claim 53, modified Dewhirst teaches the method of claim 52 substantially as claimed. Dewhirst further teaches wherein the thermally triggered nanoparticles are thermosensitive liposomes (see Fig. 4, pages 746-747, thermosensitive liposomes (i.e. nanoparticles) are loaded with a drug and delivered intravascularly to a tumor region where heat is applied to cause hyperthermia that releases the drug from the liposome).
Regarding claim 55, modified Dewhirst teaches the method of claim 52 substantially as claimed. However, modified Dewhirst fails to expressly state wherein the at least one anti- cancer agent has an extraction ratio of more than 0.3 (30%).
Dewhirst teaches that the at least one anti-cancer agent is delivered and released intravascularly (see Dewhirst pages 746-747). Thus, the extraction ratio of the at least one anti-cancer agent is a result effective variable in that adjusting the extraction ratio affects the ability of the method to treat tumors and its ability to be cleared without accumulating in the bloodstream which could result in toxicity. Further, it appears that one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of modified Dewhirst to include an extraction ratio within the claimed range as it involves adjusting a parameter which is capable of adjustment. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include wherein the at least one anti-cancer agent has an extraction ratio of more than 0.3 (30%) as a matter of routine optimization since it has been held that "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Further, Applicant appears to place no criticality on the range claimed, stating that an extraction ratio within the claimed range is preferable but that the specific range is not a critical requirement of the invention (see Specification page 6 lines 216-231, page 10 lines 393-402).
Regarding claim 56, modified Dewhirst teaches the method of claim 52 substantially as claimed. Dewhirst further teaches wherein the at least one anti-cancer agent comprises doxorubicin (see Fig. 4, pages 746-747, thermosensitive liposomes (i.e. nanoparticles) are loaded with doxorubicin).
Regarding claim 57, modified Dewhirst teaches the method of claim 52 substantially as claimed. Modified Dewhirst further teaches wherein the near-infrared energy has one or both of a predetermined duration or a predetermined magnitude (see Fig. 4, page 746, at least a predetermined duration is discussed).
Regarding claim 58, modified Dewhirst teaches the method of claim 52 substantially as claimed. Modified Dewhirst further teaches wherein the applying the near-infrared energy is configured to expose the tissue to at the penetration depth in the range from 0.5 to 3 cm from the surgical cavity surface to hyperthermia in a range from 40 to 50 °C (see Dewhirst page 746, see previous modifications in view of Li in the rejection of claim 52 above, see Li Introduction).
Regarding claim 59 modified Dewhirst teaches the method of claim 52 substantially as claimed. Modified Dewhirst fails to expressly state monitoring temperature of the tissue by one or more of an infrared camera or a temperature probe placed at or near the surgical cavity surface.
Peyman teaches a method (see par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]) comprising monitoring temperature of the tissue by one or more of an infrared camera or a temperature probe placed at or near the surgical cavity surface (see par. [0084], [0136], [0200], [0215]-[0216], and [0276]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to comprise monitoring temperature of the tissue by one or more of an infrared camera or a temperature probe placed at or near the surgical cavity surface, as taught by Peyman, because monitoring temperature can minimize and prevent pain and overheating (see Peyman par. [0084]).
Regarding claim 60, modified Dewhirst teaches the method of claim 52 substantially as claimed. Modified Dewhirst further teaches wherein targeting the near-infrared energy comprises exposing the selected tissue region to the near-infrared energy to heat the selected tissue region and induce release of the at least one anti-cancer agent from the thermally triggered nanoparticles (see Dewhirst pages 746-747, the hyperthermia is applied locally to release the drug where the hyperthermia is applied; see previous modifications in rejection of claim 52 above).
However, modified Dewhirst fails to expressly state selecting a tissue region comprising at least a part of the surgical cavity surface before targeting the near-infrared energy based on an image acquired of the tissue before applying the near-infrared energy.
Peyman teaches a method (see par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]), comprising selecting a tissue region comprising at least a part of the surgical cavity surface before targeting the near-infrared energy based on an image acquired of the tissue before applying the near-infrared energy (see par. [0136] and [0215]-[0216]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include selecting a tissue region comprising at least a part of the surgical cavity surface before targeting the near-infrared energy based on an image acquired of the tissue before applying the near-infrared energy, as taught by Peyman, in order to allow for enhanced imaging of the tumor while simultaneously providing the drug delivery therapy (see Peyman par. [0136]).
Regarding claim 61, modified Dewhirst teaches the method of claim 52 substantially as claimed. Modified Dewhirst further teaches wherein the at least one anti-cancer agent is fluorescent or tagged with a fluorescent marker, the method further comprising fluorescence imaging to visualize a location and a quantity of the at least one anti-cancer agent one or both of during or after the applying the near-infrared energy (see Fig. 4, pages 746-747, the liposomes can also include an MR contrast agent or radionuclide for direct visualization of drug delivery in near real time; see previous modifications in rejection of claim 52 above).
Regarding claim 62, modified Dewhirst teaches the method of claim 61 substantially as claimed. However, modified Dewhirst fails to state modifying one or more of an intensity, a location, or a duration of the near-infrared energy based on the fluorescence imaging to promote delivery of the at least one anti-cancer agent to the tissue.
Peyman teaches a method (see par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]) comprising modifying one or more of an intensity, a location, or a duration of the near-infrared energy based on the fluorescence imaging to promote delivery of the at least one anti-cancer agent to the tissue (see par. [0084], [0200], and [0276]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to comprise modifying one or more of an intensity, a location, or a duration of the near-infrared energy based on the fluorescence imaging to promote delivery of the at least one anti-cancer agent to the tissue, as taught by Peyman, in order to minimize and prevent pain and overheating (see Peyman par. [0084]).
Regarding claim 63, Dewhirst discloses a method (see Fig. 4, pages 746-747) comprising:
infusing thermally triggered nanoparticles incorporating at least one anti-cancer agent, wherein the thermally triggered nanoparticles are configured for intravascular triggered release, into systemic blood circulation (see Fig. 4, pages 746-747, thermosensitive liposomes (i.e. nanoparticles) are loaded with a drug and delivered intravascularly to a tumor region where heat is applied to cause hyperthermia that releases the drug from the liposome and the released drug diffuses across the vessel wall and into the tumor); and
releasing the at least one anti-cancer agent from the thermally triggered nanoparticles and across a vessel wall into a tissue surrounding a tumor by applying a drug-releasing energy, wherein the at least one anti-cancer drug once released is configured to kill remnant cancer cells in the tissue (see Fig. 4, pages 746-747, thermosensitive liposomes (i.e. nanoparticles) are loaded with a drug and delivered intravascularly to a tumor region where heat is applied to cause hyperthermia that releases the drug from the liposome and the released drug diffuses across the vessel wall and into the tumor).
While Dewhirst teaches that surgery in combination with delivery of anti-cancer agents can influence the effectiveness of chemotherapeutic treatment (see page 738, col. 1; "In order for cancer chemotherapy to have lasting effects, drugs must be applied to a large fraction (close to 100%) of cancerous cells. Many factors influence the effectiveness of chemotherapeutic treatment, including the use of radiation, surgery or other treatments in combination with chemotherapy"), Dewhirst fails to expressly state that the at least one anti-cancer drug is released into a tissue surrounding a surgically extracted tumor, wherein the at least one anti-cancer drug once released is configured to kill remnant cancer cells in the tissue. Dewhirst further fails to state applying the drug-releasing energy up to a penetration depth in a range from 0.5 cm to 3 cm from a surface of the tissue.
Peyman teaches a method (see par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]) wherein the at least one anti-cancer drug is released into a tissue surrounding a surgically extracted tumor, wherein the at least one anti-cancer drug once released is configured to kill remnant cancer cells in the tissue (see par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Dewhirst to include wherein the at least one anti-cancer drug is released into a tissue surrounding a surgically extracted tumor, wherein the at least one anti-cancer drug once released is configured to kill remnant cancer cells in the tissue, as taught by Peyman, because surgery in combination with chemotherapy can influence the effectiveness and long- term effects of the chemotherapy (see Dewhirst page 738, col. 1) and such a combination can include surgical excision of the tumor prior to performing the nano- particle delivery and application of the release-triggering energy near the surgical site (see Peyman par. [0024]-[0025], [0125]-[0127], and [0177]-[0178]).
However, modified Dewhirst still fails to state applying the drug-releasing energy up to a penetration depth in a range from 0.5 cm to 3 cm from a surface of the tissue.
Li teaches a method (see abstract) comprising applying a drug-releasing energy up to a penetration depth in a range from less than 1 cm or 3 cm (see Introduction, “The tissue penetration depth of effective PTTAs in the first near-infrared (NIR-I, 650-950 nm) window is often less than 1 cm, while the second NIR (NIR-II, 1000–1700 nm) laser can penetrate a depth of 3–5 cm [12]”).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include a penetration depth of less than 1 cm or 3 cm, which falls within the claimed range, as taught by Li, because Li teaches that a penetration depth of less than 1 cm or 3 cm is effective for NIR applicators for cancer treatment depending on the type of NIR used (Li; see Introduction, “The tissue penetration depth of effective PTTAs in the first near-infrared (NIR-I, 650–950 nm) window is often less than 1 cm, while the second NIR (NIR-II, 1000–1700 nm) laser can penetrate a depth of 3–5 cm [12]”).
Regarding claim 64, modified Dewhirst teaches the method of claim 63 substantially as claimed. However, modified Dewhirst fails to expressly state wherein the applying the drug-releasing energy comprises using a near-infrared laser.
Peyman teaches a method (see par. [0125]-[0127]) wherein the applying the drug-releasing energy comprises using a near-infrared laser (see par. [0084], [0125]- [0127], [0200], and [0276]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include wherein the applying the drug-releasing energy comprises using a near-infrared laser, as taught by Peyman, because near-infrared radiation is another form of energy suitable for inducing hyperthermia to release drugs from thermally triggered nanoparticles (see Peyman par. [0039], [0125]-[0127], and [0276]).
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Dewhirst et al. ("Transport of drugs from blood vessels to tumour tissue") in view of Peyman (US 2016/0022976 A1) and further in view of Paulides et al. (“Recent technological advancements in radio-frequency- and microwave-mediated hyperthermia for enhancing drug delivery”), as applied to claim 36 above, further in view of Burke et al. (“Drug release kinetics of temperature sensitive liposomes measured at high-temporal resolution with a millifluidic device”).
Regarding claim 41, modified Dewhirst teaches the method of claim 36 substantially as claimed. However, modified Dewhirst fails to expressly state wherein the nanoparticles are configured to release more than 50% of the at least one anti-cancer agent within 10 seconds in response to the release-triggering energy.
Burke teaches a method for treating cancerous or precancerous cells in a patient (see Introduction, “Temperature sensitive liposomes (TSL) are a promising drug delivery system for enhancing delivery of chemotherapy to solid tumours. When exposed to temperatures at or above the lipid solid-to-liquid phase transition temperature (typically above 40 ˚C), pores are thought to form in the lipid membrane triggering release of the encapsulated drug [1–5]. As such, administration of TSL in combination with applied mild hyperthermia to the tumour results in tumour- localised drug delivery.”) wherein the nanoparticles are configured to release more than 50% of the at least one anti-cancer agent within 10 seconds in response to the release-triggering energy (see page 791, Fig. 5b shows that at least Calcein and Dox satisfy the claimed release rate; see page 793, Fig. 8b shows that at least MPPC-LTSL satisfies the claimed release rate and Fig. 9 shows that MPPC-LTSL at 41-45˚C satisfies the claimed release rate).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to configure the release kinetics of the nanoparticles to release more than 50% of the at least one anti-cancer agent within 10 seconds in response to the release-triggering energy, as taught by Burke, in order to allow the majority of the drug to be released in the location where drug uptake takes place (see Burke, Introduction, “This intravascular triggered release mechanism is most effective if the majority of the drug is released from TSL during transit of the heated target region (transit time) where release and drug uptake takes place. Since mean transit times for most tumours are in the range of a few seconds, comprehensive evaluation of drug release from TSL formulations requires measurements at much shorter heating times than reported in prior studies”; see also Discussion on pages 790-791).
Claim 50 is rejected under 35 U.S.C. 103 as being unpatentable over Dewhirst et al. ("Transport of drugs from blood vessels to tumour tissue") in view of Peyman (US 2016/0022976 A1) and further in view of Li et al. (“Recent advances in the development of near-infrared organic photothermal agents”), as applied to claim 46 above, further in view of Sharma (US 2022/0151674 A1).
Regarding claim 50, modified Dewhirst teaches the method of claim 46 substantially as claimed. Modified Dewhirst further teaches wherein exposure of internal tissue below the surgical cavity surface to the near-infrared radiation is configured to cause hyperthermia in the internal tissue adequate for inducing release of the doxorubicin from the thermosensitive liposomes (see Dewhirst Fig. 4, Dewhirst pages 746-747, thermosensitive liposomes are delivered intravascularly to a tumor region where heat is applied to cause hyperthermia that releases doxorubicin from the thermosensitive liposomes; see previous modifications in rejection of claim 46 above).
However, modified Dewhirst fails to expressly state applying convective air cooling with air to cool the surgical cavity surface concurrently with the targeting of the near-infrared radiation onto the surgical cavity surface.
Sharma teaches a method comprising applying convective air cooling with air to cool the surgical cavity surface concurrently with the targeting of the hyperthermia onto the surgical cavity surface (see par. [0007], [0127] and [0134]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to include applying convective air cooling with air to cool the surgical cavity surface concurrently with the targeting of the hyperthermia onto the surgical cavity surface, as taught by Sharma, in order to maintain that the radiation is applied only to the target area (see Sharma par. [0134]). Since modified Dewhirst's hyperthermia is induced by the near-infrared radiation (see previous modifications in rejection of claim 46 above), this combination teaches that the applying convective air cooling is concurrent with the targeting of the near-infrared radiation.
Claims 54 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Dewhirst et al. ("Transport of drugs from blood vessels to tumour tissue") in view of Peyman (US 2016/0022976 A1) and further in view of Li et al. (“Recent advances in the development of near-infrared organic photothermal agents”), as applied to claims 52 and 64 above, further in view of Burke et al. (“Drug release kinetics of temperature sensitive liposomes measured at high-temporal resolution with a millifluidic device”).
Regarding claim 54, modified Dewhirst teaches the method of claim 52 substantially as claimed. However, modified Dewhirst fails to expressly state wherein the thermally triggered nanoparticles are configured for intravascular release of more than 50% of the at least one anti-cancer agent within 10 seconds when exposed to temperatures in a range from 40 to 45 ˚C.
Burke teaches a method (see Introduction, “Temperature sensitive liposomes (TSL) are a promising drug delivery system for enhancing delivery of chemotherapy to solid tumours. When exposed to temperatures at or above the lipid solid-to-liquid phase transition temperature (typically above 40 ˚C), pores are thought to form in the lipid membrane triggering release of the encapsulated drug [1–5]. As such, administration of TSL in combination with applied mild hyperthermia to the tumour results in tumour- localised drug delivery.”) wherein the thermally triggered nanoparticles are configured for intravascular release of more than 50% of the at least one anti-cancer agent within 10 seconds when exposed to temperatures from 40 to 45 ˚C (see page 793, Fig. 9 shows that MPPC-LTSL at 41-45˚C satisfies the claimed release rate).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to configure the release kinetics of the thermally triggered nanoparticles to release more than 50% of the at least one anti-cancer agent within 10 seconds when exposed to temperatures in a range from 40 to 45 ˚C, as taught by Burke, in order to allow the majority of the drug to be released in the location where drug uptake takes place (see Burke, Introduction, “This intravascular triggered release mechanism is most effective if the majority of the drug is released from TSL during transit of the heated target region (transit time) where release and drug uptake takes place. Since mean transit times for most tumours are in the range of a few seconds, comprehensive evaluation of drug release from TSL formulations requires measurements at much shorter heating times than reported in prior studies”; see also Discussion on pages 790-791).
Regarding claim 65, modified Dewhirst teaches the method of claim 64 substantially as claimed. However, modified Dewhirst fails to expressly state wherein the thermally triggered nanoparticles are thermosensitive liposomes configured for intravascular triggered release of more than 50% of the at least one anti-cancer drug within 5 seconds when exposed to temperatures above 40 ˚C.
Burke teaches a method (see Introduction, “Temperature sensitive liposomes (TSL) are a promising drug delivery system for enhancing delivery of chemotherapy to solid tumours. When exposed to temperatures at or above the lipid solid-to-liquid phase transition temperature (typically above 40 ˚C), pores are thought to form in the lipid membrane triggering release of the encapsulated drug [1–5]. As such, administration of TSL in combination with applied mild hyperthermia to the tumour results in tumour- localised drug delivery.”) wherein the thermally triggered nanoparticles are thermosensitive liposomes configured for intravascular triggered release of more than 50% of the at least one anti-cancer drug within 5 seconds when exposed to temperatures above 40 ˚C (see page 793, Fig. 9 shows that MPPC-LTSL at 41-45˚C satisfies the claimed release rate).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of modified Dewhirst to configure the release kinetics of the thermally triggered nanoparticles to release more than 50% of the at least one anti-cancer drug within 5 seconds when exposed to temperatures in above 40 ˚C, as taught by Burke, in order to allow the majority of the drug to be released in the location where drug uptake takes place (see Burke, Introduction, “This intravascular triggered release mechanism is most effective if the majority of the drug is released from TSL during transit of the heated target region (transit time) where release and drug uptake takes place. Since mean transit times for most tumours are in the range of a few seconds, comprehensive evaluation of drug release from TSL formulations requires measurements at much shorter heating times than reported in prior studies”; see also Discussion on pages 790-791).
Response to Arguments
Applicant’s arguments, see Remarks pages 8-10, filed 3/18/2026, with respect to the rejection(s) of claim(s) 36, 46, 52, and 63 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of 35 U.S.C. 103.
Applicant’s arguments, see Remarks pages 10-11, filed 3/18/2026, with respect to the rejection(s) of claim(s) 41, 54, and 65 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of 35 U.S.C. 103.
Conclusion
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/AVERY SMALE/Examiner, Art Unit 3783
/KAMI A BOSWORTH/Primary Examiner, Art Unit 3783
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